Dissolution specifications based on release rates.

Abstract

A procedure based on release rates is proposed for the establishment of dissolution specifications that ensure the bioequivalence of a test and a reference product. This procedure, which confines Cmax (the maximum concentration of the drug in vivo) and AUCinfinity (the area under the time-concentration curve, extrapolated to infinity) values within any desired range (relative to a reference product), can be used as an alternative to the methods presented in the FDA guidance1 or the USP.2 The method is appropriate for zero-order or first-order release products with linear Level A in vitro/in vivo correlations (IVIVC). Based on the result that the relative difference in Cmax must always be smaller than the relative difference in the absorption rate constants (for any test and reference products of a given drug), the "minimum range" specifications are set. These specifications, which are identical for both zero-order and first-order release products, are of general validity. They depend only on the relative extents of release, but are otherwise drug or formulation independent. For certain extended release products demonstrating a constant release rate that is unaffected by dissolution conditions (thus allowing the assumption of Level A IVIVC), the "minimum range" dissolution limits are applicable even when in vivo data is not available. If the reference product in vivo data is available, wider limits (which are product specific) may be set. If the drug disposition is monoexponential, the specifications generated are the widest possible. They are termed the "ideal" specifications. In the case of a multiexponential disposition, the limits set by the procedure will (generally) not be the widest possible. Although the method is based on one-compartment models, it is essentially model independent in the sense that microscopic modeling is redundant for its application.