Developing Discriminatory Drug Dissolution Tests and Profiles: Some Thoughts for Consideration on the Concept and Its Interpretation

Drug dissolution (or release) testing is an analytical technique used to assess release profiles of drugs in pharmaceutical products,generally solid oral products such as tablets and capsules (1). This test gains its significance from the fact that if a drug from a product is to produce its effect, it must be released from the product and should generally be dissolved in the fluids of the gastrointestinal (GI) tract. Thus,a drug dissolution test may be considered as an indicator of potential drug release and absorption characteristics of a product in humans as well as in animals (2–6). Therefore,a dissolution test is often considered a surrogate for the assessment of availability of drugs in the body,generally termed bioavailability (7). This link of dissolution (in vitro) to drug release in the body (in vivo) as commonly determined by bioavailability assessment is formally referred to as in vitro–in vivo correlation (IVIVC). This concept of IVIVC, in a quantitative and/or qualitative format,provides the basis for the assessment of quality of the products. Thus,the dissolution test is not only a procedure for product development but is also extensively used as a quality control technique because of this in vitro–in vivo association. To reflect drug absorption behaviour in vivo or,more accurately drug release in vivo,drug dissolution tests are conducted in vitro,mimicking the physiological environment of the GI tract. The GI tract environment is represented by mild stirring of drug products in aqueous-based solutions,such as 0.1 N HCl or buffers having pH values in the range of 4–7.5. The cumulative percentage of a drug dissolved at a number of time points is determined and may be reported as a plot of % drug dissolved versus sampling times. The resulting graph is commonly referred to as a “dissolution profile”and provides a means of comparison with in vivo drug release to establish absorption characteristics of drugs from products in humans (6,8–9). Further,because of the above-mentioned in vitro–in vivo association, it is generally considered that if a dissolution profile of a test product matches that of a reference product, then the test product should behave similarly to the reference product in vivo (i.e.,both will have similar bioavailabilities and will be considered as bioequivalent). Conversely, if the profile of the test product is different from that of the reference product,then the test product might behave differently in humans. This practice of describing dissolution results or profiles is commonly referred to as providing discriminating dissolution profiles,and the test as a discriminatory test. That is,a dissolution test is expected to discriminate whether dissimilar products are from different manufacturing batches of the same product or from different products such as generics. It is most important to note that the terminology of “discrimination”should be related to and based on similarity or dissimilarity of in vitro results to in vivo results only. It is further important to note that a test should only be considered discriminatory if dissolution profiles obtained are dissimilar for dissimilar in vivo profiles (i.e.,products should be bioinequivalent). If different dissolution profiles are obtained for products with the same or different formulations or manufacturing attributes but with similar in vivo characteristics,they may not be considered as discriminating profiles,and the test that produces such profiles should not be considered as a discriminatory test. The differences in profiles for products having similar release characteristics in vivo (i.e., for bioequivalent products) should be considered as an expected and acceptable variation in dissolution results from acceptable products without any negative therapeutic consequences. Such differences in dissolution profiles should ABSTRACT Drug dissolution profiles are increasingly used to evaluate drug release characteristics of pharmaceutical products. Discriminatory dissolution profiles are highly desirable for differentiating between products having differences in pharmaceutical attributes (formulation and/or manufacturing processes differences) that may reflect corresponding differences in vivo. Commonly in the literature,differences in the profiles based only on pharmaceutical attributes have also been described as discriminatory. This appears to have created confusion in properly defining and developing discriminating profiles. This article should help to clarify definition/concept,independent of the apparatus or procedure used,so that proper discriminating profiles may be developed for improved evaluation of pharmaceutical products.