In Vivo Predictive Dissolution – Flux Measurements

14:25 - 15:05

 

Amount and the rate of absorption for the active pharmaceutical ingredient (API) to the blood circulation from the orally administered drug products is determined by the flux of API through epithelial lining of the small intestine. The flux values would depend on the amount of the dissolved API available at the site of permeation as well as on the rate with which drug penetrates the membranes separating GIT from blood capillaries. The former quantity is governed by dissolution and solubility of API in the corresponding medium at biorelevant load while the latter is determined by effective permeability of the compound through the biological membranes.

Establishing meaningful correlations between in vivo absorption and in vitro measurements have been presenting a significant challenge for pharmaceutical researchers especially when dealing with low soluble compounds. One of the reason is that in many cases the effect of solubilizing formulations was studied through USP-type dissolution measurements without taking into account biorelevant dissolution medium/volume parameters and interconnection between formulation additives and dissolution/solubility/permeability values.

This presentation introduces principles and devices that can be utilized for flux measurements in a systematic and reproducible manner. Measuring flux and its dependence on formulations allows assessment of complex interplay between solubility, permeability and dissolution rate in formulation development. The case will be made that flux measurements can be used for early prediction of fraction absorbed, formulation ranking, bioequivalence study risks, drug-drug interactions from pH modifying agents and other biorelevant in vitro studies.

Konstantin Tsinman, Chief Scientific Officer, Pion