Excipient chelating agents

Ophthalmic ointments usually contain petrolatum as the base. The petrolatum is sterilized by dry heat and combined with the sterile dmg powder under aseptic conditions. Ophthalmic suspensions contain very fine (- 10 ji) particle sized soHds suspended in an aqueous vehicle. The vehicle is adjusted to isotonicity and viscosity-increasing excipients, chelating agents, and surfactants also may be needed. The aqueous vehicle in these cases is generally autoclaved and mixed with sterile dmg powder asceptically (30). 

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. 

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. 

As a guide to formulation development, studies should be undertaken to evaluate the contribution of candidate excipients, including preservatives, antioxidants, chelating agents, cosolvents, and buffers on compound stability and solubility. This is particularly important in the development of suspensions for nebulization. Compatibility with packaging components also needs to be considered as a matter of priority. Peptides and proteins in particular are notorious in their ability to adsorb onto a variety of surfaces, particularly plastic. 

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. 

In contrast to these studies where decreases in oral bioavailability are correlated with complex formation, increasing the solubility of norfloxacin using speciflc solubility enhancers has been shown to increase the oral bioavailability [29, 42, 43]. Both EDTA (p.srai 1-7) and sodium caprate (caprylic acid pA a 5) were thought to act as chelating agents to increase the dissolution of norfloxacin into aqueous media [42]. The combinations of norfloxacin and either EDTA or sodium caprate were dosed as mixed powders in capsules. While both excipients increased the oral bioavailability of norfloxacin in rabbits, sodium caprate was more effective than EDTA (sodium... 

One of the critical factors in excipient selection and concentration is the effect on preferential hydration of the biopharmaceutical product [53, 54], Preferential hydration refers to the hydration layers on the outer surface of the protein and can be utilized to thermodynamically explain both stability enhancement and denatur-ation. Typical excipients used in protein formulations include albumin, amino acids, carbohydrates, chelating and reducing agents, cyclodextrins, polyhydric alcohols, polyethylene glycol, salts, and surfactants. Several of these excipients increase the preferential hydration of the protein and thus enhance its stability. Cosolvents need to be added in a concentration that will ensure their exclusion from the protein surface and enhance stability [54], A more comprehensive review of excipients utilized for biopharmaceutical drug products is available elsewhere [48],... 

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