Dissolution testing development

G. Levy, J. R. Leonards, and J. A. Procknal, Development of in vitro dissolution tests which correlate quantitatively with dissolution rate-limited drug absorption in man, J. Pharm. Sci., 54, 1719-1722 (1966). K. A. Javaid and D. E. Cadwallader, Dissolution of aspirin from tablets containing various buffering agents, J. Pharm. Sci., 61, 1370-1373 (1972). 

S. Riegelman, Dissolution Testing in Drug Development and Quality Control, The Academy of Pharmaceutical Sciences Task Force Committee, American Pharmaceutical Association, 1979, p. 31. 

M Aikman, L Augsburger, I Berry et al. Collaborative development of two-tiered dissolution testing for gelatin capsules and gelatin-coated tablets using enzyme-containing media. Pharmacop Forum 24(5) 7045-7050, 1998. 

The information requirements for products such as prolonged-release oral dosage forms will depend on whether or not it has been possible, during the development of the product, to establish an in vivo-in vitro correlation between clinical data and dissolution studies. In vivo-in vitro correlations should be attempted using product at different stages of development, but bioavailability and pharmacokinetics data from pivotal clinical studies using at least pilot-scale production materials and possibly routine production material are particularly important. Where it is not possible to establish an in vivo-in vitro correlation, additional data will be required to compare the bioavailability of product developed at laboratory scale, pilot scale, and production scale. In the absence of an in vivo-in vitro correlation, the dissolution test will be a quality control tool rather than a surrogate marker for in vivo performance of the product. 

Dissolution test data will be required in all cases (and for all strengths of product) for development and routine control and should be based on the most suitable discriminatory conditions. The method should discriminate between acceptable and unacceptable batches based on in vivo performance. Wherever possible Ph Eur test methods should be used (or alternatives justified). Test media and other conditions (e.g., flow through rate or rate of rotation) should be stated and justified. Aqueous media should be used where possible and sink conditions should be maintained. A small amount of surfactant may be added where necessary to control surface tension or for active ingredients of very low solubility. Buffer solutions should be used to span the physiologically relevant range—the current advice is over pH 1 6.8 or perhaps up to pH 8 if necessary. Ionic strength of media should be reported. The test procedure should employ six dosage forms (individually) with the mean data and a measure of variability reported. 

The sponsor of an NDA will normally have extensive pharmacokinetic and pharmacodynamic information available at the time the NDA is submitted. It may be appropriate to use data such as the slope of the dose-response curve in support of a contention that, for example, dissolution testing may be, in some instances at least, be sufficient for the demonstration of development bioequivalency. Certainly, we may conclude that the requirements for development bioequivalence should never be more rigorous than those applied in consideration of generic bioequivalency. 

The BCS has been developed primarily for regulatory applications, although its use has been extended beyond this area (as discussed in more detail below). The aim of the BCS in a regulatory context is to provide a basis for replacing certain bioequivalence studies by equally or more accurate in vitro dissolution tests. This could reduce costs and time in the development process as well as reducing unnecessary drug exposure in healthy volunteers, which is normally the study population in bioequivalence studies. 

In vitro dissolution testing is an important tool in the development of solid drug products, as well as in batch quality controls. The aim of the test is to see that the drug is appropriately dissolved in the gastrointestinal tract and made available for absorption. It is therefore highly desirable that the in vitro tests provide data that correlate to the in vivo situation. However, attainment of IVIVC has often failed-and the concept of IVIVC has been challenged. 

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