Excipient antioxidants

One of the most important advantages of HPLC over spectrophoto-metric methods lies in its specificity and selectivity due to its separation capability. Through chromatographic separations, the analytes of interest can be detected and quantified without interference from the typical matrix that includes excipients, antioxidants, preservatives, and dissolution media. Ion-pair HPLC was used to monitor the dissolution of pentamidine from EVA sustained-release film where polymeric matrices could create significant bias if a spectrophotometric method were used. Due to their strong UV absorbance, the antioxidants and preservatives (e.g., BHA, BHT, ascorbic acid and propyl gallate) are often the major... 

Note for Guidance on Excipients, Antioxidants, and Antimicrobial Preservatives in the Dossier for Marketing Authorization of a Medicinal Product. The European Agency for the Evaluation of Medicinal Products, 2003. 

CPMP (2003) Note for guidance on excipients, antioxidants and antimicrobial preservatives in the dossier for application for marketing authorization of a medicinal product. CPMP/QWP/419/03. Accessible by www.ema.europe.eu... 

Single-dose preparations intended for use in eye surgery do not contain excipient ingredients, in order to avoid tissue irritation. However, multiple-dose containers may require antioxidants (qv), antimicrobial preservatives, or buffers to maintain stabiHty and stefiHty. Such solutions are packaged in polyethylene flexible dropper units called droptainers or in glass dropper botdes. 

The choice of the excipients and their concentration, including their function (e.g., antimicrobial preservatives, antioxidants. ..). In the case of antimicrobial preservatives, data are expected on the preservative efficacy in products on storage, including after reconstitution or dilution and during the period of use. 

With the exception of antimicrobial preservatives and antioxidants (see below) and coloring matter (for which an identity test should be available), it is not normally necessary to test for the presence of excipients in finished products. 

Where antioxidants or antimicrobial preservatives are used, the finished product release specification will need to include identification tests and assays for these two types of excipient. The shelf life specification should also include a specification for assay for antimicrobial preservatives. Stability data will be required for both antioxidants and antimicrobial preservatives in the finished product, and in addition the preservative efficacy of the formulated product should be examined over its shelf life and by means of appropriate in-use stability tests. Preservative efficacy data should also be presented at the lower limit of the preservative assay. 

Antioxidants should be used only when it can be shown that their incorporation cannot be avoided by appropriate manufacturing methods or packaging. Their intended performance in the product should be clearly stated—e.g., whether for the benefit of the active ingredient or an excipient. Their efficacy can depend on their nature, their concentration (subject to safety considerations), when they are incorporated in the manufacture of the finished product, the container, and the formulation (particularly their compatibility with other constituents). All of these issues should be addressed. Their activity should also be determined in the finished product under conditions simulating the use of the product. The extent of degradation should be determined with and without the antioxidant. 

Compatibility of the excipients and active ingredient is addressed (but often with little detail). Formulation optimization and excipient ranges may be included in the discussion. The inclusion of antioxidants in the formulation is discussed as appropriate. 

Parenterais The most important criterion for parenterals is that they have to be sterile for injection or infusion administration. Excipients are added to make parenterals isotonic with blood, improve solubility, and control pH of the solution. The solvent vehicles include water-for-injection, sterile sodium chloride, potassium chloride, or calcium chloride solution, and nonaqueous solvents such as alcohol, glycol, and glycerin. Preservatives, antioxidants, and stabilizers are normally added to enhance the properties of the drug product. 

The extent of revalidation required for formulation changes should be determined on a case-by-case basis. Slight adjustments to the formulation may not require further validation work. This would include an adjustment of the excipient ratios, a change in tablet shape, etc. Specificity and accuracy should be re-evaluated for the inclusion of a new excipient into the formulation (e.g., antioxidants, dyes, preservatives). A change in the formulation such as going from a tablet to a capsule or from a liquid to a solid would mean a significant change to the formulation and complete validation should be performed. 

A preservative is a substance that prevents or inhibits microbial growth and extends the shelf life of the drug products. In most pharmaceutical drug products, only a few compounds are typically selected as preservatives. For efficiency, a generic method should be developed for the types of preservatives that are more commonly used. For example, butylated hydroxytoluene (BHT) is an antioxidant commonly used in many solid dosage formulations to retard oxidative degradation of the excipients. 

Additives are all formulation constituents other than the active ingredient. Although additives could be classified into excipients and vehicles (excipients for solid preparations and vehicles for liquid ones), there are several other agents used in pharmaceutical formulations with specific functions such as preservatives, sweeteners, coatings, colorants, antioxidants, surfactants, emulsifying agents, and flavors. Since they comprise a vast amount of products, this section will deal with additives for compounding pharmaceutical products for internal use only [17,18]. 

Antioxidants are often used to reduce oxidation of active substances and excipients in creams. There most common types of oxidants have been recognized (24). Table 1 lists each class of antioxidants and the most common antioxidants used in pharmaceutical creams. 

Some excipients such as tocophersolan polyethylene glycol succinates (17) or polyethylene glycol hydroxystearates (18) that are used as antioxidants or to increase the solubility of hydrophobic drugs also possess the pharmacological property to attenuate the P-glycoprotein-mediated multidrug resistance (19,20). 

Pure carbon spheres of Cf,(l the fullerenes—react avidly with free radicals with a higher antioxidant ability than the naturally occurring vitamin E (21). Endohedral fullerenes have been shown to be capable of encapsulating a variety of atoms such as radiotracers or noble gases, thereby making them efficient excipients in the delivery of radioisotopes to cancer cells or in magnetic resonance imaging (MRI) (22). 

Companies that manufacture food additives will often also produce an excipient grade. Many excipients first found application in processed foods where their demonstrated safety has made them attractive for use as pharmaceutical excipients. Examples of food additives also used in drug products include artificial sweeteners, antioxidants, and inorganic salts. 

Once good physical stability of an emulsion is insured, its commercialization mandates chemical stability of the incorporated drug and other essential components for at least 18 months. Key factors that affect the chemical stability of pharmaceutical emulsions include drug stability in oil, drug stability in aqueous media, drug concentration in oil and emulsion, phase volume ratio, droplet size, presence of excipients, and presence of air and/or peroxide radicals. As mentioned earlier, choice of appropriate antioxidant is important. 

Several good surfactants in terms of solubility, compatibility, and toxicity can be selected for prototype formulation development. In general, one surfactant can be used as the primary solubilizer in a prototype formulation. Functional excipients, such as antioxidants, tonicity agents for parenteral products and sweeteners, and taste masking agents for oral products, may be added to the prototyp formulation. 

Nebulizer solutions are often presented as concentrated solutions from which aliquots are withdrawn for dilution before administration. Such solutions require the addition of preservatives, e.g. benzalkonium chloride, and antioxidants (e.g. sulphites). Both excipient types have been implicated with paradoxical bronchospasm and hence the current tendency to use small unit-dose solutions that are isotonic and free from preservatives and antioxidants. 

Vitamin A occurs as a light yellow to red oil that may solidify on refrigeration (liquid form). In solid form it may have the appearance of the diluent that has been added to it. It is a suitable form or derivative of retinol (C20H30O Vitamin A alcohol). It usually consists of retinol or esters of retinol formed from edible fatty acids, principally acetic and palmitic acids, or mixtures of these. It may be diluted with edible oils, or it may be incorporated in solid edible carriers, extenders, or excipients. It may contain suitable preservatives, dispersants, and antioxidants, providing it is not to be used in foods in which such substances are prohibited. In liquid form it is... 

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