In vitro-in vivo correlation of a modified-release oral form of ketotifen: in vitro dissolution rate specification

The dissolution rate profile of a new modified-release (MR) oral tablet of ketotifen (Zaditen SRO tablet, Sandoz Ltd.) was determined under different conditions (pH, rpm, paddle or basket) with the U.S.P. apparatus. Three different variants of MR tablets were tested. In addition, the in vivo bioavailabilities of these MR tablets were evaluated after a single-dose administration under different conditions (fasting state, with food in morning and/or evening). Several possibilities were evaluated to obtain a correlation between in vitro and in vivo data of the three MR tablets. An excellent linear correlation (r = 0.997) was obtained between the cumulative dissolved percent in vitro and the cumulative absorbed percent in vivo at each time under certain conditions. This was obtained in vitro with the dissolution rate performed in distilled water (37 degrees C) with the U.S.P. apparatus 2 (rotating paddle) and in vivo after a single-dose administration in the morning, fasting state. On the basis of this correlation, of the in vitro dissolution rate for a given variant, and of a simple method of calculation, a reliable prediction of the plasma concentrations obtained following a single dose or at steady state was found. The reliability of this prediction was validated from variants of MR tablet presenting different in vitro dissolution rate profiles and with an upscaled batch which was tested in vivo. This result allows the specifications (upper and lower limits) of the dissolution rate for the MR tablet to be defined and ensures good in vivo characteristics for the different batches of Zaditen SRO tablets during manufacture.