Formulations critical excipients

Because particle size is so intimately intertwined with powder performance, it is one of the prime considerations in selecting excipients to develop or improve a formulation. This is particularly important with direct compression formulations where excipient flowability and compaction performance are critical. Typically, excipients for these applications exhibit narrow size distributions with moderate-to-coarse particle size, having a mean size from 100 to 200 pm. 

For nebulizer and other aqueous aerosol products that use suspension systems, excipients are used to influence particle physical and chemical stability (e.g., microcrystalline cellulose for nasal sprays). The suitability of the physicochemical properties of these critical excipients should be thoroughly investigated and documented (12). Far more excipients have been included in formulations designed for nasal administration (Table 4). 

As discussed above, testing to conform to pharmacopeia requirements may not be sufficient to assure excipient quality in the manufacture of low-dose formulations. Often, excipients make the bulk of the dosage form and if a dry blending and direct compression is utilized, the functional properties of excipients become even more critical compared to a granulation process. Typical functional properties to be tested for excipients include the following ... 

Binders are just one of the critical excipients for a successful wet granulation formulation, as they are used to create an ordered mixture of all the ingredients by creating a cohesive network. While more than 30 different materials have been studied over the years, currently there are only about a dozen binders that are commonly used as granulating agents and these can be subdivided into three main categories, (/ sugars such as... 

Most of these studies require analysis of the formulation in terms of the potency assay of the drug substance and other critical excipients. Consequently, an analytical method such as HPLC is required. 

Other additives such as antimicrobial agents, antioxidants, buffers and tonicity-adjusting agents can be included in injection formulations and it is the responsibility of the pharmacist to check that all excipients and adjuvants are suitable (benzyl alcohol, ethanol, sulfites, sodium content, etc.). Nevertheless, one is left with a difficult choice over excipients, either those for which toxicity is known and therefore predictable, or those with safety profiles that have not been established in children (see under Critical excipients, page 55). The pH and osmo-larity of the preparation must also be checked before administration by another route. 

Another aspect of polysorbates is that they are inherently susceptible to oxidative degradation. Often, as raw materials, they contain sufficient quantities of peroxides to cause oxidation of protein residue side chains, especially methionine (59). The potential for oxidative damage arising from the addition of stabilizer emphasizes the point that the lowest effective concentrations of excipients should be used in formulations. For surfactants, the effective concentration for a given protein will depend on the mechanism of stabilization. It has been postulated that if the mechanism of surfactant stabilization is related to preventing surface-denaturation, the effective concentration will be around the detergent s critical micellar concentration. Conversely, if the mechanism of stabilization is associated with specific protein-detergent interactions, the effective surfactant concentration will be related to the protein concentration and the stoichiometry of the interaction (39). 

Obviously, each material in a formulation can be characterized in this way by use of instrumented press studies and Ileckel plot analysis in research and development. This approach can be of use to formulators in selecting specific excipients for specific drug entities. However, the characterization and performance of the final formulation are the critical measurements in the scale-up/production compaction operation. 

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