The Relationship Between In Vitro Drug Dissolution and In Vivo Absorption

Abstract

The rate at which a drug enters the bloodstream is an important characteristic of any drug product because it may have a marked influence on the biological response elicited by the drug. Before entering the bloodstream a solid dosage form (tablet or capsule) must first dissolve and then the drug in solution is absorbed into the blood. Drugs whose rate of absorption is much faster than the dissolution rate are said to be dissolution limited because the rate of entry of the drug into the blood is limited by the dissolution process rather than the absorption process. Such drugs are of great interest in the pharmaceutical industry because the rate of dissolution is amenable to control by means of the formulation. In the case of dissolution-limited drugs there may be a relationship between the absorption in human subjects (in vivo) and the dissolution under laboratory conditions (in vitro). The current methodology used to establish such a relationship (known as a level A in vivo–in vitro correlation) has several deficiencies from a statistical viewpoint. This level A in vivo–in vitro correlation corresponds to the coincidence of the mean in vivo–in vitro dissolution profiles which can be tested by using standard statistical procedures for the analysis of such repeated measures data. Two such approaches are considered, i.e. Hotelling’s T2-test and mixed effects modelling. These methods are compared with the current methodology by means of a simulation experiment used to generate the operating characteristic curves.