In the present drug discovery and development, most of the candidates are poorly soluble in water, hence can result in poor bioavailability. Various approaches such as change in pH, temperature, use of surfactants and biorelevant media have been employed since they mimic the gastrointestinal conditions. Surfactants when dissolved in water self-aggregate to form micelles at critical micelle concentration. The drug molecule gets solubilized in these micelles depending upon their affinity towards the surfactant molecules either at the hydrophobic core, hydrophilic surface, or intermediate positions in the micelles. But these media often fail for IVIVC because their composition may not account dose proportionality seen in vivo, and also in presence of surfactants, it is the free form that is available for absorption and hence the therapeutic effect and not the drug that is bound to the micelles. Therefore, we need to understand how pH-dependent drugs behave in presence of different and varying concentration of surfactant since different drugs interact uniquely with a surfactant, depending on the pH of the solution, ionic nature and the chemical properties of the drug and surfactant. Various methods have to been employed to measure the drug concentration in systems containing surfactants, but they tend to overestimate or underestimate the data therefore pulsatile microdialysis is used to determine the free concentration of the drug available for absorption in these systems.

This project focuses on determining the distribution of the drug between the micellar and aqueous phase for three different poorly soluble drugs---a weakly acidic drug (ibuprofen), a weakly basic drug (benzocaine) and a neutral drug (griseofulvin) in different media containing varying concentration of drug and nonionic surfactant SLS (sodium lauryl sulfate). The surfactant concentrations ranged from 2mM to 30mM, which for these systems was from slightly below the critical micelle concentration (CMC) to somewhat above it. (For these systems, the CMCs ranged from about 2 to about 5 mM.) IBU concentrations ranged from 10-20microg/mL for pH 2 and 20-80microg/mL for pH 7 at 23 and 37°C. It is seen that at low pH most of the drug is unionized and bound to the hydrophobic core of the micelles but at high pH the drug is present in the aqueous media than bound to micelles due to the ionic interaction (repulsive) between the drug and the surfactant molecules and due to the affinity of the ionized drug towards the solvent. The amount of drug entrapped in micelles and the amount available in the free form was quantified by a parameter calledf D, obtained by pulsatile microdialysis method, which is defined as the concentration of the drug in the aqueous phase divided by the total drug concentration (i.e., the total amount of drug divided by the total volume of the aqueous plus micellar systems).

In case of benzocaine, the concentrations ranged from 100-400microg/mL in solutions at pH 1.5 and pH 7, at 23 and 37°C. This molecule is highly ionized at low pH, and through drug distribution studies we saw that even though the drug was ionized, it had more affinity towards the micellar phase than towards the aqueous solvent. Since the drug and the surfactant are opposite in charge, there is a decrease in the repulsive forces between the head group of the surfactant molecules, contributing to micellization process and thus decreasing the CMC value of the surfactant. Here the drug may be bound to micelles in the hydrophobic core as well as on the hydrophilic surface part of the micelles at low pH but whereas at high pH the deposition in the micelles may be only due to hydrophobic interaction which is also seen in case of griseofulvin.

This data was further supported by measuring surfactant tension and particle size of the micellar systems. By plotting surface tension vs. SLS concentration, we were able to calculate the CMC concentration for each system. It is observed that pH of the solution can show a significant influence on the CMC value of the surfactant and hence the solubility of the drugs and the amount available for absorption. Hence, through PMD, we were able to measure the change in the concentration of drug available for absorption in the presence of varying factors such as pH, temperature, drug and surfactant concentration.

Finally, the interaction between the drugs and surfactants was assessed by testing a phase equilibrium (partitioning model). The data showed that the micelles behaved like discrete phases into which the drugs partitioned. This was of interest because the surfactant concentrations were only slightly above the CMC, and for some solutions (such as benzocaine 400 microg/mL) the drug concentration was close to the CMC.