Antioxidants and Chelating Agents

Excipients such as buffers, antimicrobials, antioxidants and chelating agents may be required for optimal drug stability in IDDS formulations. Several unique criteria when selecting excipients must be considered. 

Lachman L. Antioxidants and chelating agents as stabilizers in liquid dosage forms. Drug Cosmet Ind 1968 102(2) 43-45,146—149. 

Citric, ascorbic, and phosphoric acids are added to chelate the trace metals, particularly copper and iron, to retard the initiation step. Mixtures of antioxidants and chelating agents act synergistically, that is, the combination is more effective than the sum of the individual compounds. A commercial mixture recommended by the American Meat Institute and sold as Tenox or Sustane is 20% BHA, 6% propyl gallate, and 4% citric acid in propylene glycol. The propylene glycol is added to solubilize the citric acid in the oil. 

The oil phase preferably includes mineral oil, petrolatum, cetyl alcohol, or stearyl alcohol. Emulsifiers such as polysorbate 80, sorbitan monostearate, or others known in the art may be used. Buffering agents, antioxidants, and chelating agents may be added to improve the characteristics of the formulation. 

Antioxidants and chelating agents. Antioxidants inhibit the oxidative reactions in oils, fats and waxes that lead to rancidity, with its distinctively unpleasant smell. Due to their reducing properties, antioxidants only exhibit weak anti-microbial efficacy. However, they can enhance the efficacy of certain preservatives, such as Bronopol [II, 17.14.], German 115 [II, 3.4.7.], Glydant [II, 3.4.9.] and Kathon CG [II, 15.3.], allowing a reduction of the... 

Ascorbic acid is widely used as a food additive due to its properties (vitamin, antioxidant and chelating agent), especially in canning... 

Mineral oil and paraffins should not be used, because these are not metabolized and may irritate tissue. Various other additives are needed for stabiUty, stefihty, and isotonicity antimicrobial preservatives, antioxidants (qv), chelating agents (qv), and buffers. No parenteral container material is completely inert to parenteral solvent systems. 

As metal ions catalyze peiroxidation reactions, glass-distilled water should be used and chelating agents can be added to the medium. (5) The dispersions should not be exposed to y irradiation. (6) Antioxidant can be added to the system. a-Tocopherol, buty-lated hydroxytoluene, butyl hydroxyanisole, and ascorbic acid have been proposed as antioxidants. 

Buffers can also be provided in parenteral formulations to ensure the required pH needed for solubility and/or stability considerations. Other excipients included in parenteral products are preservatives (e.g., benzyl alcohol, p-hydroxybenzoate esters, and phenol), antioxidants (e.g., ascorbic acid, sodium bisulfite, sodium metabisulfite, cysteine, and butyl hydroxy anisole), surfactants (e.g., polyoxyethylene sorbitan monooleate), and emulsifying agents (e.g., polysorbates). An inert gas (such as nitrogen) can also be used to enhance drug stability. Stability and solubility can also be enhanced by the addition of complexation and chelating agents such as the ethylenediaminetetraacetic acid salts. For a more detailed list of approved excipients in parenteral products, the reader should consult the monographs within the USP. 

Control of physical and/or chemical deterioration by addition of antioxidants, stabilisers, emulsifiers and chelating agents. 

Protein instability mechanisms have been reviewed by several investigators.3-13 Chemical reactions such as oxidation, deamidation, proteolysis, racemization, isomerization, disulfide exchange, photolysis, and others will give rise to chemical instability. It is critical that when this happens, the denaturation mechanisms must be identified in order to select appropriate stabilizing excipients. These chemical excipients may be in the form of amino acids, surfactants, polyhydric alcohols, antioxidants, phospholipids, chelating agents, and others. 

The use of quenching agents in polymers is a recent development. Of particular interest are the nickel(II) chelates in polypropylene film and fibre and the even newer hindered amines which appear to combine the roles of antioxidant and quenching agent. 

The molecular mechanism of enzymatic isomerization is far from being fully understood. In a study of Pseudomonas sp. strain E-3 the similarity between cis-trans isomerase and LOX was hypothesized on the basis of the common inhibition given by antioxidants. However, chelating agents, which do not affect isomerization, also inhibit LOX. A second mechanistic hypothesis was then formulated, consisting of the hydration-dehydration mechanism, similar to the formation of 3-trans-enoyl-CoA from the corresponding cis isomer [28]. Another recent mechanism was proposed based on analysis of carbon isotope fractionation of CTI [25]. Scheme 6.3 shows the proposed mechanism of CTI based on the enzyme-substrate complex as an intermediate, which allows the rotation of the carbon-carbon double bond to occur. 

The preferred mode to prevent oxidation is to overlay the prodnct with nitrogen or argon. However, dissolved oxygen in the solution and trace metals from the sugars or buffer ingredients conld accelerate oxidation. Hence, it may be essential to add antioxidants or chelating agents like ethylene diamine tetraacetic acid (EDTA). 

Chem. Descrip. Triisodecyl phosphite CAS 25448-25-3 EiNECS/ELiNCS 246-998-3 Uses Heat stabilizer for polyolefins, PU, PVC, PET, coatings, lubricants improves color in rigid and plasticized PVC chelating agent with metal carboxylates as polymer additives, esp. for chlorinated polymers such as PVC and chlorinated PE antioxidant and EP agent for lubricants Properties APHA 50 max. clear liq. sp.gr. 0.884-0.904 (25/15.5 C) dens. 7.4 Ib/gal vise. 15 cps acid no. 0.05 max. flash pt. (COC) 420 F ref. index 1.4530-1.4610 6.2% P Toxicology Skin irritant... 

The inhibitors of oxidation reaction of fats are substances which reduce the oxidation rate, regardless of the mechanism of their action. These compounds include antioxidants, synergists, chelating agents and compounds decomposing hydroperoxides by nonradical reactions. Also agents stabiHsing hydroperoxides may reduce the reaction rate because they inhibit the formation of free radicals. 

Certain compounds, known as chelating agents (qv), react synergisticaHy with many antioxidants. It is beheved that these compounds improve the functional abiUties of antioxidants by complexing the metal ions that often initiate free-radical formation. Citric acid and ethylenediaminetetraacetic acid [60-00-4] (EDTA), C2QH2gN20g, are the most common chelating agents used (22). 

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