CRITICAL DISSOLUTION TESTS OF ORAL SYSTEMS BASED ON STATISTICALLY DESIGNED EXPERIMENTS - III - IN-VITRO IN-VIVO CORRELATION FOR MULTIPLE-UNIT CAPSULES OF PARACETAMOL BASED ON PLS MODELING

The main aims of the present study were to establish an in vitro/in vi vo correlation for multiple-unit capsules of paracetamol by means of s tatistical prediction models and to investigate the effect of a number of in vitro variables on the discussion rate of paracetamol from the formulation. A fractional factorial screening design was used to inves tigate the effects of the variables agitation, pH, osmolality, viscosi ty, and the presence of bile salt on the dissolution rate of paracetam ol. The effects were evaluated in two separate partial least-squares m odels, in which the responses were expressed as the cumulative percent age of paracetamol dissolved at specified time-points (model I) and as the shape (beta) and scale (eta) parameters according to the Weibull function (model II). It was concluded that agitation and viscosity had significant effects on the dissolution rate of paracetamol. Statistic al models based on the responses from models I and II were then used t o predict the in vitro conditions most closely correlated with the in vitro dissolution of paracetamol after administration of the formulati on to 10 healthy volunteers. The predicted optimal in vitro conditions were similar for the two models and not too far from what is expected from the gastrointestinal tract. The experimental verification of the in vitro conditions showed that both models were equally good, and co ntributed to high degrees of correlation with the in vivo dissolution behavior of the formulation during 9 hr. The relationships obtained wh en plotting the percentage dissolved in vitro versus in vivo were y = 1.1x (r(2) = 0.98) and y = 1.1x (r(2) = 0.94) for models I and II, res pectively. Based on these results, it is difficult to state a preferen ce for one of the models. Finally, the use of statistical prediction m odels to develop critical in vitro tests is a successful approach in t he establishment of associations between dissolution behavior in vitro and in vivo for oral extended-release systems.