Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`Third Edition .
`
`Edited by
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`Department of Pharmaceutical Sciences
`Wilkes University School of Pharmacy
`Wilkes-Barre, Pennsylvania
`
`ARIA
`
`American Pharmaceutical Association
`Washington, D.C.
`
`(RP)
`
`Pharmaceutical Press
`
`London, United Kingdom
`
`FlatWing Ex. 1011, p. 1
`
`

`

`Published by the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DC 20037-2985, USA
`www.aphanet.org
`and the Pharmaceutical Press
`1 Lambeth High Street, London SE1 7JN, UK
`www.pharmpress.com
`
`© 1986, 1994, 2000 American Pharmaceutical Association and Pharmaceutical Press
`
`First edition 1986
`Second edition 1994
`Third edition 2000
`
`Printed in the United States of America
`
`ISBN: 0-85369-381-1 (UK)
`ISBN: 0-917330-96-X (USA)
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients / edited by Arthur H. Kibbe.--3rd ed.
`p. ; cm.
`Includes bibliographical references and index.
`ISBN 0-917330-96-X
`1. Excipients--Handbooks, manuals, etc.
`Pharmaceutical Association.
`[DNLM: 1. Excipients--Handbooks. QV 735 H236 2000]
`RS201.E87 H36 2000
`615'.19--dc21
`
`I. Kibbe, Arthur H. II. American
`
`A catalogue record for this book is available from the British Library.
`
`99-044554
`
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or
`by any means, without the prior written permission of the copyright holder. The publisher makes no representation, express or
`implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or
`liability for any errors or omissions that may be made.
`
`Managing Editor:
`Copyeditor:
`Indexer:
`Compositor:
`Cover Designer:
`
`Melanie Segala
`Paul Gottehrer
`Lillian Rodberg
`Roy Barnhill
`Tim Kaage
`
`FlatWing Ex. 1011, p. 2
`
`

`

`Edetic Acid
`
`1. Nonproprietary Names
`BP: Edetic acid
`USP: Edetic acid
`
`2. Synonyms
`Edathamil; EDTA; ethylenediaminetetraacetic'acid; (ethylene-
`dinitrilo)tetraacetic acid; Questric acid 5286; Sequestrene AA;
`tetracemic acid; Versene Acid.
`
`3. Chemical Name and CAS Registry Number
`N,N- 1,2 -Ethanediylbis[N -(carboxymethyl)glycine] [60 -00 -4]
`
`4. Empirical Formula Molecular Weight
`292.24
`
`C 10H 1 6N208
`
`5. Structural Formula
`
`0
`0 (cid:9)
`II
`II,-., (cid:9)
`,CHI C— OH
`HO— C— `-ri2 (cid:9)
`,N— CH2- CH2-NN
`HO— C— CH2 (cid:9)
`CH2— C— OH
`II (cid:9)
`II
`0 (cid:9)
`0
`
`6. Functional Category
`Chelating agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Edetic acid and edetate salts are used in pharmaceutical formula-
`tions, 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 seques-
`tering. The stability of the metal-edetate complex depends on the
`metal ion involved and also on the pH. The calcium chelate is rel-
`atively 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 syn-
`ergists by sequestering trace amounts of metal ions, particu-
`larly 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%
`w/v. Edetates have been used to stabilize: ascorbic acid; cor-
`ticosteroids; epinephrine; folic acid; formaldehyde; gums and
`resins; hyaluronidase; hydrogen peroxide; oxytetracycline;
`penicillin; salicylic acid, and unsaturated fatty acids. Essential
`oils may be washed with a 2% w/v solution of edetate to
`remove trace metal impurities.
`
`Edetic Acid 191
`
`Edetic acid and edetates possess some antimicrobial activity
`but are most frequently used in combination with other anti-
`microbial 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 of 0.01-0.1% w/v 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% w/v are used in small volumes for
`hematological testing and 0.3% w/v in transfusions.
`
`8. Description
`Edetic acid occurs as a white crystalline powder.
`
`9. Pharmacopeial Specifications
`
`Test
`
`BP
`
`USP
`
`Identification
`Appearance of solution
`Residue on ignition
`Sulfated ash
`Heavy metals
`Nitrilotriacetic acid
`Iron
`Chloride
`Loss on drying
`Assay
`
`5. 0.2%
`5 20 ppm
`_5 200 ppm
`5 80 ppm
`5 200 ppm
`5 0.1%
`98.0-101.0%
`
`_5 0.2%
`—
`5 0.003%
`.5 0.3%
`5 0.005%
`
`98.0-100.5%
`
`10. Typical Properties
`Acidity/alkalinity:
`pH = 2.2 for a 0.2% w/v aqueous solution.
`Antimicrobial activity: edetic acid has some antimicrobial activity
`against Gram-negative microorganisms, Pseudomonas aerugi-
`nosa, some yeasts, and fungi, although this activity is insufficient
`for edetic acid to be used effectively as an antimicrobial preser-
`vative on its own.(1,2) However, when used with other antimicro-
`bial 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; bronopol; cetrimide; imidurea; para-
`bens; and phenols, especially chloroxylenol. Typically, edetic
`acid is used at a concentration of 0.1-0.15% w/v. In the presence
`of some divalent metal ions, such as Ca24" or Mg2+, the synergistic
`effect may be reduced or lost altogether. The addition of diso-
`dium 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 bactericidal.
`Dissociation constant:
`PKa1 = 2.00;
`pica = 2.67;
`plc3 = 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.
`
`FlatWing Ex. 1011, p. 3
`
`(cid:9)
`(cid:9)
`

`

`192 Edetic Acid
`
`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 wa-
`ter 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 ster-
`ilized by autoclaving, and should be stored in an alkali-free
`container.
`Edetic acid and edetates should be stored in well-closed con-
`tainers in a cool, dry, place.
`
`12. Incompatibilities
`Edetic acid and edetates are incompatible with strong oxidiz-
`ing agents, strong bases, and polyvalent metal ions such as
`copper, nickel, and copper alloy.
`Edetic acid and disodium edetate behave as weak acids, dis-
`placing 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 di-
`sodium edetate has also been reported to be incompatible with
`amphotericin and with hydralazine hydrochloride in infusion
`fluids.
`
`13. Method of Manufacture
`Edetic acid may be prepared by the condensation of ethyl-
`enediamine with sodium monochloroacetate in the presence
`of sodium carbonate. An aqueous solution of the reactants is
`heated to about 90°C for 10 hours, then cooled, and hydro-
`chloric acid added to precipitate the edetic acid.
`Edetic acid may also be prepared by the reaction of ethylene-
`diamine with hydrogen cyanide and formaldehyde with sub-
`sequent 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 exten-
`sively 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-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. (5)
`Edetates, particularly disodium edetate and edetate calcium diso-
`dium, 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 pharmaceutical formulations.
`Disodium edetate, trisodium edetate, and edetic acid readily che-
`late calcium and can, in large doses, cause calcium depletion (hy-
`pocalcemia) 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 ede-
`tate 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 mg/kg body-
`weight. (6)
`See also Section 19.
`LD50 (mouse, IP): 0.25 g/kg(7)
`LD50 (mouse, oral): 0.03 g/kg
`LD50 (rat, IP): 0.397 g/kg
`
`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. In-
`gestion, 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.
`
`17. Pharmacopeias
`Br, Ger, and US.
`
`18. Related Substances
`Dipotassium edetate: C 10H14K2N208
`Molecular weight: 368.46
`CAS number: [2001-94-7]
`Synonyms: dipotassium edathamil; dipotassium ethylenedi-
`aminetetraacetate; edathamil dipotassium; edetate dipotas-
`sium; edetic acid dipotassium salt; EDTA dipotassium;
`N,AT/-1,2-ethanediylbis[N-(carboxymethyl)glycine] dipotas-
`sium salt; ethylenebis(iminodiacetic acid) dipotassium salt;
`ethylenediaminetetraacetic acid dipotassium salt; (ethyl-
`enedinitrilo)tetraacetic acid dipotassium salt; tetracemate
`dipotassium.
`Appearance: white crystalline powder.
`Disodium edetate: C 10H14N2Na208
`Molecular weight: 336.21
`CAS number:
`[139-33-3] for the anhydrous material;
`[6381-92-6] for the dihydrate.
`Synonyms: disodium edathamil; disodium ethylenediaminetetraace-
`tate; edathamil disodium; edetate disodium; edetic acid disodium
`salt; EDTA disodium; N,N'-1,2-ethanediylbis [N-(carboxy-
`methyl)glycine] disodium salt; ethylenebis(iminodiacetic acid)
`disodium salt; ethylenediaminetetraacetic acid disodium salt;
`(ethylenedinitrilo)tetraacetic acid disodium salt; Questal Di;
`Sequestrene NA2; tetracemate disodium; Versene disodium.
`Appearance: odorless white crystalline powder with a slightly
`acid taste.
`Pharmacopeias: Eur, Int, Jpn, Pol, and US.
`
`FlatWing Ex. 1011, p. 4
`
`

`

`Acidity/alkalinity: pH = 4.3-4.7 for a 1% w/v solution in car-
`bon dioxide free water.
`Freezing point depression:
`0.14°C (1% w/v aqueous solution)
`Melting point:
`decomposition at 252°C for the dihydrate.
`Refractive index:
`1.335 for a 1% w/v aqueous solution.
`Solubility: practically insoluble in chloroform and ether;
`slightly soluble in ethanol (95%); soluble 1 in 11 of water.
`Specific gravity:
`1.004 for a 1% w/v aqueous solution.
`Viscosity (kinematic): 1.03 mm2/s (1 cSt) for a 1% w/v aque-
`ous solution.
`Method of manufacture: disodium edetate may be prepared by
`the reaction of edetic acid and sodium hydroxide.
`Safety: see also Section 14.
`LD50 (mouse, IP): 0.26 g/kg( 1)
`LD50 (mouse, IV): 0.056 g/kg
`LD50 (mouse, oral): 2.05 g/kg
`LD50 (rabbit, 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
`preparations, 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% w/v.
`Edetate calcium disodium: C10H12CaN2Na208
`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 ethyl-
`enediaminetetraacetate; calcium disodium (ethylenedinitrilo)tet-
`raacetate; edathamil calcium disodium; edetic acid calcium
`disodium salt; [V,N-1,2-ethanediylbis[N-(carboxymethyl)glyci-
`nato]](4-)-N,N',0,0',ON,-ONicalciate(2-)disodium; EDTA cal-
`cium; ethylenediaminetetraacetic acid calcium disodium chelate;
`[(ethylenedinitrilo)tetraacetato]calciate(2-) disodium; sodium cal-
`ciumedetate; Versene CA.
`Appearance: white or creamy-white colored, slightly hygro-
`scopic, crystalline powder or granules; odorless, or with a
`slight odor; tasteless, or with a faint saline taste.
`Pharmacopeias: Eur, Pol, and US. Some pharmacopeias spec-
`ify that edetate calcium disodium is the dihydrate, others
`that it is the anhydrous material. The USP 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/cm3
`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 pre-
`pared by the addition of calcium carbonate to a solution
`of disodium edetate.
`Safety: see also Section 14.
`LD50 (dog, oral): 12 g/kg(7)
`
`Edetic Acid 193
`
`LD50 (mouse, IP): 4.5 g/kg
`LD50 (mouse, oral): 10 g/kg
`LD50 (rabbit, IP): 6 g/kg
`LD50 (rabbit, oral): 7 g/kg
`LD50 (rat, IP): 3.85 g/kg
`LD50 (rat, IV): 3.0 g/kg
`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 Ingredi-
`ents Guide (injections, oral capsules, solutions, suspen-
`sions, 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 for-
`mulations in preference to disodium edetate or sodium ede-
`tate 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 anhy-
`drous material.
`Sodium edetate: C1oH12N2Na408
`Molecular weight: 380.20
`CAS number: [64-02-8]
`Synonyms: edetate sodium; edetic acid tetrasodium salt; EDTA
`tetrasodium; N,N'-1,2-ethanediylbis[N-(carboxymethyl)gly-
`eine] tetrasodium salt; ethylenebis(iminodiacetic acid) tet-
`rasodium salt; ethylenediaminetetraacetic acid tetrasodium
`salt; (ethylenedinitrilo)tetraacetic acid tetrasodium salt;
`Sequestrene NA4; tetracemate tetrasodium; tetracemin; tet-
`rasodium edetate; tetrasodium ethylenebis(iminodiacetate);
`tetrasodium ethylenediaminetetraacetate; Versene.
`Appearance: white crystalline powder.
`Acidity/alkalinity:
`pH = 11.3 for a 1% w/v aqueous solution.
`Melting point: > 300°C
`Solubility: soluble 1 in 1 of water.
`Safety: see also Section 14.
`LD50 (mouse, IP): 0.33 g/kg( 7)
`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 triva-
`lent metallic ions to form soluble metal chelates and is
`used in pharmaceutical formulations in concentrations
`between 0.01-0.1% w/v.
`Trisodium edetate: C1oH13N2Na308
`Molecular weight: 358.20
`CAS number: [150-38-9]
`Synonyms: edetate trisodium; edetic acid trisodium salt; EDTA
`trisodium; N,N=1,2-ethanediylbis[N- (carboxymethyDgly-
`eine] trisodium salt; ethylenediaminetetraacetic acid triso-
`dium salt; (ethylenedinitrilo)tetraacetic acid trisodium salt;
`trisodium ethylenediaminetetraacetate;
`Sequestrene NA3;
`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 add-
`ing a solution of sodium hydroxide to disodium edetate.
`Safety: see also Section 14.
`LD50 (mouse, IP): 0.3 g/kg( 7)
`LD50 (mouse, oral): 2.15 g/kg
`LD50 (rat, oral): 2.15 g/kg
`
`FlatWing Ex. 1011, p. 5
`
`

`

`194 Edetic Acid
`
`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 sodi-
`um, 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 max-
`imum daily dose of 3 g, has been used as a treatment for
`hypercalcemia. For the treatment of lead poisoning, a dose of
`60-80 mg/kg of edetate calcium disodium, as a slow infusion
`in two daily doses, for 5 days, has been used.
`
`20. Specific References
`1. Richards RME, Cavill RH. Electron microscope study of effect
`of benzalkonium chloride and edetate disodium on cell enve-
`lope of Pseudomonas aeruginosa. J Pharm Sci 1976; 65:
`76-80.
`2. Whalley G. Preservative properties of EDTA. Mfg Chem 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 Pharmacol 1972; 24(Suppl): 84P-89P.
`4. Morton DJ. EDTA reduces antimicrobial efficacy of thiomer-
`osal. Int 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. Sev-
`enteenth report of the joint FAO/WHO expert committee on
`food additives. Tech Rep Ser Wld Hlth Org 1974; No. 539.
`7. Sweet DV, editor. Registry of Toxic Effects of Chemical Sub-
`stances. Cincinnati, US Department of Health, 1987
`
`21. General References
`Chalmers L. The uses of EDTA and other chelates in industry.
`Mfg Chem 1978; 49(3): 79-80, 83.
`Hart JR. Chelating agents in cosmetic and toiletry products. Cos-
`met 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 forms. Drug Cosmet Ind 1968; 102(2): 43-45,
`146-149.
`
`22. Authors
`PJ Weller.
`
`FlatWing Ex. 1011, p. 6
`
`