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Dissolution testing is a required test currently used to demonstrate the performance of all solid oral dosage forms in which absorption of the drug is necessary for the product to exert a therapeutic effect (1). The challenge for scientists working in a research and development environment is to develop a procedure that can not only guide the formulation development process but can also be used as a regulatory test to detect manufacturing deviations and to ensure product consistency at release and over the product’s shelf life. The test must be rugged and reproducible and highlight only significant changes in product performance. The robustness of the procedure is particularly important since calibrated dissolution baths are allowed a variation of ± 2 rpm in the rotational speed of the apparatus. If a formulation is sensitive to small changes in rotational speed, then observed changes in the dissolution profile may simply reflect allowable instrument variation. The development of a dissolution procedure involves selecting the dissolution media, apparatus and agitation rate appropriate to the product. The solubility of the active ingredient(s) is one of the key aspects in the screening of possible dissolution media. USP favors media related to physiological conditions, for example buffer solutions or diluted HCl (0.01 N) (2). The dissolution characteristics of the formulation are to be evaluated over the physiologic pH range of 1.2 to 7.5 (1). For water-insoluble and sparingly water soluble drug products, use of a surfactant such as sodium lauryl sulfate is recommended (3). To ensure good mixing of the drug and excipients in the dissolution vessel, a suitable apparatus and rotational speed should be selected. The basket method (Apparatus 1) is routinely used for capsule formulations at agitation speeds of 50 and 100 rpm, while the paddle method (Apparatus 2) is used mostly for tablets dosage forms at 50 and 75 rpm (1). In general, mild agitation conditions should be maintained during dissolution testing to allow maximum discriminatory power (4). In most cases, the dissolution apparatus tends to become less discriminating when operated at faster speeds that result in a flatter drug release profile. However, for certain tablet formulations, the increased paddle speed results in a method with a higher discriminating power by reducing the variability of the data. Use of a low rotation speed could result in a lack of robustness in the data due to poor hydrodynamics in the dissolution vessel and can become more a reflection of system artifacts such as coning rather than true formulation changes. Visual observations are especially useful during method development to understand the behavior of the tablet in the dissolution vessel. The agitation speed providing optimum hydrodynamics in the vessel can be determined by comparison of the dissolution profiles obtained by making small variations in paddle speed (robustness experiments) as well as by challenging the testing procedure through the use of mismanufactured tablets (discriminatory power experiments). The final dissolution procedure should be robust and should be able to distinguish small but real changes in the product formulation. Abstract Regulatory agencies often consider USP dissolution methods developed using the slowest paddle speed (50 rpm) to represent the most appropriate operating condition since they tend to produce the steepest drug release profiles. A steep drug release profile is frequently assumed to provide optimum discriminating power either to distinguish small variations in the tablet manufacturing process or to detect stability changes on storage. However, for certain tablet formulations it has been demonstrated that drug release profiles generated at 50 rpm can in fact be a reflection of system artifacts rather than a discriminatory tool. Higher paddle speeds which result in flatter drug release profiles can, in some cases,more accurately reflect true formulation changes. This point is highlighted in the description of the development of a dissolution method for a compressed tablet containing two active pharmaceutical ingredients (API). The selection of dissolution medium for a tablet with two APIs having very different solubility properties is detailed. The effects of paddle speed on system performance and method discriminating power are critically evaluated.

Developing a Discriminating Dissolution Procedure for a Dual Active Pharmaceutical Product with Unique Solubility Characteristics