Dissolution Method for Quality Control of Immediate Release Dosage Forms 3611 Dissolution Media

Aqueous test media are generally preferred (USP, 2004; FDA, 1997b). Although the design of a dissolution test used for QC is mainly based upon the physico-chemical properties of the drug substance and the characteristics of the dosage form, it is important to select dissolution media to at least reflect the pH effect in the GI environment. For this reason, the pH of these media should be within the physiologic pH range of 1.2-6.8, where pH 1.2 and pH 6.8 represent the pH values under the gastric and intestinal conditions, respectively (FDA, 1997a). Hydrochloric acid, acetate, or phosphate buffer in the physiological pH range are commonly used and accepted as a dissolution medium for QC. The use of pure water in dissolution testing is usually not recommended primarily due to its limited buffering capacity. The volume of these dissolution media should be based upon the drug solubility, but is generally 500, 900, or 1,000 mL (FDA, 1997a). Sink conditions2 are often recommended, since the dissolution tests used for QC are intended to provide conditions under which the majority of the drug (>90%) can be released.

For some poorly soluble drugs that cannot dissolve adequately in aqueous solutions within the physiologic pH range, surfactants may be required to provide sink conditions and achieve a complete drug dissolution within reasonable time. The surfactants, such as sodium lauryl sulfate (SLS) and Tween, can be used to improve the dissolution rate by acting as a wetting agent and/or increasing the solubility of poorly soluble compounds through reduction of the interfacial tension and induction of micellar formation (Shah et al., 1989; Sievert and Siewert, 1998). They may also be used to improve the correlation between the in vitro dissolution data and in vivo drug product performance (Brown et al., 2004), as will be explained below. The level and solubilizing capacity of a surfactant are critical

2 The term sink conditions is generally referred to as the condition where the medium volume is at least greater than three times that needed to form a saturated solution of a drug substance.

to QC. When the level and/or the solubilizing capacity of the surfactant is too high, the dissolution media may not be able to adequately discriminate differences among formulations, such as changes in the polymorphic form or particle size, as suggested in ICH Q6A. For hard and soft gelatin capsules as well as gelatin-coated tablets, a specific amount of enzyme(s) may be added to the dissolution medium to prevent pellicle formation.

3.6.1.2 Apparatus and Test Conditions

The most commonly used dissolution apparatus for solid oral dosage forms are the basket method (USP Apparatus I), the paddle method (USP Apparatus II), the reciprocating cylinder (USP Apparatus III) and the flow-through cell system (USP Apparatus IV). The first two apparatus are commonly used for dissolution testing of immediate-release dosage forms. The major advantage of these two devices is that they are simple, robust, and well standardized. The reciprocating cylinder apparatus has also been used for the dissolution testing of immediate-release products of highly soluble drugs, such as metoprolol and ranitidine, and some immediate-release products of poorly soluble drugs, such as acyclovir (Yu et al., 2002). However, this apparatus should be considered only when the basket and paddle method are shown to be unsatisfactory. Due to the potential need for the large volume of medium, the flow-through cell system is not suitable for a dissolution test that is used routinely for the QC purpose. Nevertheless, the reciprocating cylinder device and the flow-through cell system may offer some advantages for their use in a biorelevant method, as will be discussed below.

For QC or drug product release testing, mild agitation conditions should be maintained during dissolution testing using the basket and paddle methods to allow maximum discriminatory power. If the rotational speed is too low, coning may occur, which leads to a low dissolution rate. However, if the rate of rotation is too fast, the test will not be able to discriminate the differences between the acceptable and not acceptable formulations or batches. The common stirring speed used for Apparatus I is 50-100 rpm, while with Apparatus II the common stirring speed is 50-75rpm (FDA, 1997a). All dissolution tests should be performed at physiological temperature (37 ± 0.5 °C). The test duration ranges from 15 min to 1 h.

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