Limitations of Quality Control Dissolution Tests

There are some issues regarding the current use of dissolution tests that were developed for QC. Because these dissolution tests are developed to provide a maximum discriminatory power to assess any formulation changes and manufacturing process deviations, they are often overly discriminating, meaning that the differences detected by these dissolution tests may not have any clinical relevance. For instance, in the FDA-sponsored studies of metoprolol (Rekhi et al., 1997), although the slow-dissolving tablets of metoprolol failed the USP dissolution test, the in vivo pharmacokinetic studies showed that all metoprolol tablets were bioequivalent with their corresponding formulations regardless of their in vitro dissolution rates. Thus, these clinically insignificant differences detected by the overly discriminating dissolution test often lead to the rejection of batches that may have an acceptable clinical performance. In addition, dissolution specifications, which are established based upon acceptable clinical, pivotal bioavailability, and/or bioequivalence batches using such overly discriminating dissolution tests, may not truly reflect the in vivo performance of a drug product. As a consequence, without a detailed knowledge on how dissolution affects the bioavailability of the drug product, these specifications are usually set to be very tight to assure the product quality and consistency by identifying any possible subtle changes in the product attributes before in vivo performance is affected. These shortcomings further facilitate the need for the development of biorelevant dissolution tests.

Dissolution tests used for QC can also be subjected to the limitation of being nondiscriminating. This limitation becomes evident if testing conditions are not selected appropriately (e.g., the agitation rate or surfactant level). This situation is best illustrated by the case of mebendazole (Swanepoel et al., 2003). Mebendazole, which is a broad-spectrum anthelmintic drug, exists in three polymorphic forms (A, B, C) that display solubility and therapeutic differences. Among these three forms, polymorph C is therapeutically favored. Despite these differences, the three polymorphs produced similar dissolution profiles using a dissolution method that employed 0.1N HCl with 1% SLS. Specifically, all these dissolution profiles met the specification in which 75% of the drug dissolved within 120 min. It has been understood that the use of a large amount of SLS

in the dissolution medium eliminates the differences in the dissolution rates of mebendazole polymorphs.

The precision and accuracy of dissolution testing are often very sensitive to several subtle operational controls. These include, but are not limited to the eccentricity of the agitating element, vibration, stirring element alignment, stirring rate, dosage form position, sampling probes, position, and filters. These factors may have a significant effect on the dissolution measurement if they are not controlled properly. For instance, the study of nondisintegrating double layered tablets containing salicylic acid indicates that the stirring rate and basket placement influence the drug dissolution in the basket apparatus (Howard et al., 1979; Mauger et al., 1979). In addition, the hydrodynamics in the paddle apparatus have been shown to be very complex and vary with site in the vessel (McCarthy et al., 2004). Therefore, the exact location where the tablet lands after it is dropped into the vessel may have a considerable influence on the velocity profile around the tablet and hence its dissolution behavior.

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