Functional Category:
Chelating agent.
Applications in Pharmaceutical Formulation
Edetic acid and edetate salts are used in pharmaceutical formulations, cosmetics, and foods as chelating agents. 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 18. Edetic acid and edetates are primarily used as antioxidant synergists, sequestering trace amounts of metal ions, particularly copper, iron, and manganese, that 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; corticosteroids; 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 and edetates possess some antimicrobial activity but are most frequently used in combination with other antimicrobial preservatives owing to their synergistic effects. Many solutions used for the cleaning, storage, and wetting of contact lenses 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.
Description
Edetic acid occurs as a white crystalline powder.
Stability and Storage Conditions
Although edetic acid is fairly stable in the solid state, edetate saltsare more stable than the free acid, which decarboxylates if heatedabove 1508C. Disodium edetate dihydrate loses water of crystallization when heated to 1208C. Edetate calcium disodium is slightlyhygroscopic and should be protected from moisture.Aqueous solutions of edetic acid or edetate salts may be sterilizedby autoclaving, and should be stored in an alkali-free container.Edetic acid and edetates should be stored in well-closedcontainers in a cool, dry place
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 total parenteral nutrition (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.
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 doserelated 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 disodium, are used in a greater number and variety of pharmaceutical formulations than the free acid. 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. 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 18. LD50 (mouse, IP): 0.25 g/kg(7) LD50 (rat, IP): 0.397 g/kg