Regulatory aspects of modified release dosage forms: special cases of dissolution testing using the flow-through system.

More than 30 years have been devoted to characterizing the biopharmaceutical properties of drug products. The numerous tests developed are generally based on two distinct methodologies--a closed system (beaker method) and an open system (flow-through method). Selected methods were finally standardized and described in such pharmacopoeias as Ph. Eur. 2, USP XXII and Ph. Jap. XII. The most common procedures are the paddle and basket methods. An alternative method--the flow--through method--was also introduced into the pharmacopoeias Ph. Eur. 2 and USP XXII. The advantages of the flow-through method are evident with regard to testing and assessing different types of dosage forms and active ingredients of very slight solubility. Changes of testing fluids (e.g. change to the pH) can be easily performed during the test. Another advantage is seen in the positioning of the specimen. Capsules, even when floating initially, or pellets can be tested using the same equipment and require no additional devices such as sinkers. With slight changes to the cell design, the same apparatus can be used for the testing of powders, or even non-solid dosage forms such as suppositories or soft-gelatine capsules. For long-term testing necessary for extended release products, flow-through apparatus offers a considerable number of advantages for routine work. Irrespective of the methodologies used, dissolution tests should be validated with regard to analytical methods, testing conditions and specifications. The validation of the analytical method should follow EC guidelines. Testing conditions should take into account the choice of the correct apparatus, dissolution media and agitation. The results of in vitro dissolution should be validated by in vivo data in an analogous sense. The practical application of flow-through apparatus is presented on the basis of various examples regarding development and batch control. The assessment of in vitro dissolution of biopharmaceutical characterization of drug substances, enteric-coated tablets, controlled release products, suppositories and implants will be discussed.