In situ characterization of free drug fractions and drug polymer binding in vitro using pulsatile microdialysis

In a drug delivery, mathematical modelling of drug release has potential to understand complex pharmaceutical dosage forms and could become integral part of product development. One of the major driving forces for the use of mathematical modelling in drug delivery is to save time and cost by minimizing number of required experimental studies to optimize existing drug product or to develop a new product. Mathematical modelling offers fundamental advantage of elucidation of underlying drug mechanism. This knowledge is of interest and could be prerequisite for an efficient improvement of the safety of new pharmaco-treatments. Trouble-shooting during formulation development can be addressed much more efficiently if there is a thorough understanding of how drug release is controlled. It is decisive to know which properties dominate for desired drug release from the formulations. One of the most important and challenging areas in the drug delivery field is to predict the release of the drug as a function of time using both simple and sophisticated mathematical models.;Drug release from formulations with polymer excipients involves two step mechanisms: first detachment of drug molecule from the solid-liquid interface to form hydrated interface. The second step is mass transport from this interface. There are various parameters such as drug diffusion coefficient, free drug fraction, polymer concentration, competition between drug-polymer and water polymer interactions. Ideally, all the parameters should be independently determined and then should be incorporated in to model to assess if the model is accurately predicts the drug release rate.;The aim of the project is to develop a mathematical model to quantify drug delivery in the presence of drug-polymer interactions, to incorporate interaction factor and how it will affect drug release and to study the factors affecting the mechanism and rates of drug release from formulations containing polymer excipients. To study this interaction requires a development of an in situ method to measure free fraction of the drug fD. Characterization of extent of binding in terms of binding constant and binding energy requires a development of a binding model.;In this study, an in situ method to determine free drug fraction fD in the presence of drug polymer interaction based on pulsatile micro dialysis (PMD) was developed. This information was essential for the formation of quantitative physical model for the release of the drug from the systems with polymer excipients and will include the effects of corrected mobility and free drug concentrations as a function of polymer concentration as well as water content at any time. Results of this research expands the application of PMD into areas such as determining transport properties of certain complicated physical or biological systems, the use of PMD as a drug delivery vehicle, and to study the effect of food interaction.