(305c) Development of a Novel Method for the Solubilization of Poorly Water-Soluble Drugs

In recent years, large portion of new drug candidates and drugs currently on the market have poorly water-soluble nature. As the low solubility in water reduces bioavailability of the drugs, improvements in the solubility as well as solubilization rate are the most important for the drug formulation. There are many techniques that improve the solubility such as mixing with an aqueous surfactant solution, dissolution with an organic solvent and successive solubilization and/or spray drying, and formation of suspension. However, the use of surfactants as well as organic solvents might suffer the residual chemicals harmful to the human body. In this study, a novel method for the solubilization of poorly water-soluble drugs that are environmentally benign was developed. The method is based on the hydrophobic interaction of poorly water soluble drugs with the hydrophobic core of water soluble polymer micelle which is formed by a lower critical solution temperature (LCST) nature of the polymer.

In this study, Soluplus^® (SOL) was used as the water-soluble polymer having a surfactant activity and LCST nature. Model drugs used as the poorly water soluble drugs is indomethacin (IND:acidic drug). One weight percent of aqueous SOL solution was maintained at a predetermined temperature, and the drug powder (as received) was added to the solution. After the predetermined duration of time with stirring at 500 rpm using a magnetic stirring tip, a white suspension was obtained. The concentration of drugs in the suspension was examined by a UV-VIS spectrophotometer, and freeze dried to examine the crystallinity of drugs in the hydrophobic core by a X-ray powder diffraction (XRD) analysis and differential scanning calorimetry (DSC). Infrared spectroscopy (FT-IR) was used to examine the interaction of drugs with the SOL. Long term stability of the suspension was also examined after predetermined time periods up to 1 month.

Suspensions were prepared with different periods of mixing (1 ~ 24 h) and different temperatures (room temperature ~ 70 ^oC). It was found that turbidity of the solution increases with the increase in stirring time regardless of the preparation temperature. At the same time, higher the temperature, shorter the time for the formation of milky white suspension of IND. Suspensions prepared at 70 ^oC and 50 ^oC achieved the IND concentration of 1000 mg/10 g in the dispersion with the 1 hr of stirring. On the other hand, suspension prepared at room temperature could achieve the value by increasing the stirring time. Further, maximum drug loading was found to be higher prepared at the higher temperatures. The mechanism of the solubilization could be explained as follows: even the poorly water soluble IND dissolves into water, and the saturated solubility increases with the increase in temperature. The incorporation of IND into the hydrophobic core of the SOL occurs via the distribution equilibrium of IND solid/water/SOL core. Thus higher the temperature, higher the water phase concentration of IND which leads to the higher distribution equilibrium concentration of IND in the SOL hydrophobic core. All samples thus prepared were stable up to 1 month and over.

The XRD measurement of the suspension prepared at 70 ^oC and 50 ^oC gave the halo pattern, which shows the amorphous state of IND/SOL mixtures. Further, no endothermic peak was observed in the DSC measurement. Therefore, it was found that the IND was solubilized in the hydrophobic core of the SOL with the amorphous state.

It could be concluded that this method is effective as a solubilization method of poorly water-soluble drugs in the suspension.