Factors Related to Drug Product Formulation

In addition to the physicochemical properties of a drug substance, inactive ingredients (or excipients) may influence the dissolution of a drug product. The effect of these excipients on the drug product dissolution rate depends on the dosage form. For immediate-release dosage forms, excipients are often used to improve the drug release from the formulation or the solubilization of a drug substance. For instance, disintegrants such as starch are often used to facilitate the break up of a tablet and promote deaggregation into granules or particles after administration (Peck et al., 1989). For poorly soluble drugs, incorporation of surfactants (e.g., polysorbate)

into the formulation may increase the dissolution rate of these products. The mechanism by which surfactants enhance the dissolution rate is to improve the solubility of the drug substance by promoting drug wetting, by forming micelles, and by decreasing the surface tension of hydrophobic drug particles with the dissolution medium (Banaker, 1991). Furthermore, coprecipitation with polyvinylpyrrolidine (PVP) has been shown to significantly influence the dissolution (Corrigan, 1985). This enhancing effect on the dissolution rate can be attributed to the formation of an energetic amorphous phase or molecular dispersion. However, some excipients may have an adverse effect on the dissolution rate. For example, lubricants such as stearates, which are used to reduce friction between the granulation and die wall during compression and ejection, are often hydrophobic in nature. Thus, these hydrophobic lubricants may affect the wettability of a drug product (Pinnamaneni etal., 2002).

For modified-release drug products, specific excipients are selected to control the rate and extent of drug release from the formulation matrix, and/or to target the delivery to selective sites in the GI tract. For instance, in matrix-based formulations, the active ingredient is embedded in a polymer matrix, which controls drug release through using mechanisms such as swelling, diffusion, erosion, or combinations (Gandhi et al., 1999). In designing these complex formulations, in addition to the characteristics of modifying release excipients, the physicochemi-cal properties of a drug substance, the interactions between the drug substance and excipients, the type of the release mechanism and the target release profile must be taken into consideration.

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