Excipient preservatives

The development of an impurity profile for a dosage form follows many of the same principles as in the drug substances however, instead of identifying all precursors and intermediates, the analyst will identify and place all of the components of the dosage form (excipients, preservatives, and others) and their affiliated impurity profiles within a master profile. Here again additional method development may be needed to... 

Pharmacopoeial methods rely heavily on simple analysis by UV/visible spectrophotometry to determine active ingredients in formulations. These methods are usually based on the use of a standard A (1 %, 1 cm) value for the active ingredient being assayed and this relies on the UV spectrophotometer being accurately calibrated as described earlier in the chapter. Such methods also presume that there is no interference from excipients (preservatives, colourants, etc.) present in formulations and that the sample is free of suspended matter, which would cause light scattering. 

Indication Active ingredient Cream trade name Structure-forming excipients Preservative... 

Figure 6.7. An example of impurities testing using gradient HPLC of a pharmaceutical product stored under accelerated stability conditions, noting the presence of excipient, preservative (butylated hydroxytoluene, BHT), impurities (Imp), and degradants (DG). HPLC conditions column Waters XTerra MS18, 150 x 3mm i.d., 3pm mobile phase (A) 16mM ammonium bicarbonate, pH 9.1 (B) acetonitrile gradient 3% B to 45% B in 25min flow rate 0.8mL/min at 50°C detection 280nm. Additional information can be obtained from reference 22.

The section includes the specifications for the raw materials and containers to be used. Preferably raw materials of a suitable pharmaceutical grade should be used (see Sect. 23.1.2), but this may not always be possible. All the considerations that played a role in the choice of the raw materials are recorded in this section, including the excipients, preservatives, colourants and flavours. Amounts and calculated doses are mentioned, and the need for specific properties (Functionally Related Characteristics) such as purity, fineness or viscosity where this is essential for the firtal quality. 

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. 

This aromatic alcohol has been an effective preservative and still is used in several ophthalmic products. Over the years it has proved to be a relatively safe preservative for ophthalmic products [138] and has produced minimal effects in various tests [99,136,139]. In addition to its relatively slower rate of activity, it imposes a number of limitations on the formulation and packaging. It possesses adequate stability when stored at room temperature in an acidic solution, usually about pH 5 or below. If autoclaved for 20-30 minutes at a pH of 5, it will decompose about 30%. The hydrolytic decomposition of chlorobutanol produces hydrochloric acid (HC1), resulting in a decreasing pH as a function of time. As a result, the hydrolysis rate also decreases. Chlorobutanol is generally used at a concentration of 0.5%. Its maximum water solubility is only about 0.7% at room temperature, which may be lowered by active or excipients, and is slow to dissolve. Heat can be used to increase dissolution rate but will also cause some decomposition and loss from sublimation. Concentrations as low as 0.125% have shown antimicrobial activity under the proper conditions. 

In general, aqueous ophthalmic solutions are manufactured by methods that call for the dissolution of the active ingredient and all or a portion of the excipients into all or a portion of the water and the sterilization of this solution by heat or by sterilizing filtration through sterile depth or membrane filter media into a sterile receptacle. If incomplete at this point, this sterile solution is then mixed with the additional required sterile components, such as previously sterilized solutions of viscosity-imparting agents, preservatives, and so on, and the batch is brought to final volume with additional sterile water. 

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. 

The incorporation of certain excipients in products is deemed to be undesirable. Examples are the inclusion of mercurial preservatives, the inclusion of benzyl alcohol in parenteral products for use in children, the use of benzoic acid esters in injections, and the inclusion of sulfites and metabisulfites in products in general. If it is intended to use any of these materials, then a full justification will be required. 

Excipients should be listed in the composition using their Ph Eur name (or one from another national pharmacopeia from an EEA member state), the International Nonproprietary Name, or an exact scientific designation, other than for materials such as preservatives or coloring agents which can be identified by an E-number. Third country pharmacopeial names may be acceptable. Coloring matter is subject to the provisions of specific legislation in the EEA. 

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. 

There are two EPARs for eyedrops. Specific issues considered for these include container composition and tamper evidence, the optimization of the formulation and manufacture, preservative and preservation issues, and justification for the use of nonterminal sterilization processes. Many of the points concerning active ingredients and excipients are similar to those discussed above. Changes in formulation during the development process (e.g., for carbomers or surfactants) are mentioned. Particle size controls for suspension products are discussed. 

A number of oral solution or suspension products are included in the EPARs. Apart from the usual points of consideration for active ingredients and excipients, particular mention is made of possible precipitation of active ingredient when a solution is in use, the inclusion of excipients having a major impact on bioavailability, the need for flavoring to mask the taste of the active ingredient, relative potency compared with other routes of administration, preservation issues, dosing devices and the precision and accuracy of the dose delivered, and bioequivalence where formulations have been modified during the development process. 

Many of these reactions are related to the quantity of excipient found in a dosage form. Benzyl alcohol benzalkonium chloride, propylene glycol, lactose, and polysorbates are all associated with dose-related toxic reactions [52-54], Large-volume parenterals containing 1.5% benzyl alcohol as a preservative have caused metabolic acidosis, cardiovascular collapse, and death in low birth weight premature neonates and infants. The cumulative dose of benzyl alcohol ranged from 99 to 234 mg/kg per day in these patients [55,56], Dose-related adverse effects to excipients are of particular concern in the preterm, low birth weight infant because... 

Formulation Aranesp is formulated as a sterile, colorless, preservative-free protein solution for intravenous (IV) or subcutaneous (SC) administration. There are two formulations the polysorbate solution includes excipients such as polysorbate 80, sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, and sodium chloride in water-for-injection while the albumin solution contains albumin, sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, and sodium chloride in water-for-injection. The pH for both formulations is 6.2 + 0.2. 

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. 

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