Critical dissolution tests of oral systems based on statistically designed experiments .1. Screening of critical fluids and in vitro in vivo modelling of extended release coated spheres

Different compositions of in vitro dissolution fluids have been developed and used in screening experiments during the development of ethylcellulose ER-coated spheres of the model drug remoxipride. The composititons were different with respect to pH, temperature, osmotic pressure, viscosity, agitation, ionic strength, polarity of the medium, type, and concentration of surfactant. By using a chemometric methodology all the variables were varied independently at the same time, and the results were connected in a mathematical model which described the experimental domain. The most significant main effects on the amount of remaxipride released at all timepoints were caused by polarity, temperature, and agitation. The mathematical model was used to predict the in vitro condititons that was best associated with the in vivo data, obtained after administration of the formulation to sixteen volunteers. A verifying experiment showed a close connection between the predicted and experimental in vitro dissolution profile up to 4 hr, but thereafter (up to 24 hr) the profiles deviated. It is obvious that the conditions need to be further optimized. However, the present approach to stress oral dosage systems during the development phase seems very promising.