Evaluation of a Miniaturized Rotating Disk Apparatus for In Vitro Dissolution Rate Measurements in Aqueous Media : Correlation of In Vitro Dissolution Rate with Apparent Solubility

Sammanfattning: The general aim of this thesis was to evaluate a newly designed and constructed miniaturized rotating disk apparatus for in vitro dissolution rate measurements of different drug substances from all of the classes in the Biopharmaceutical Classification System (BCS). The new equipment is based on a low volume flow-through cell of Plexiglas, a gold plated magnetic bar and a special designed press. The disk of drug substance (approx. 5 mg) is placed eccentrically in the bar. Rotation speeds were set with a graded magnetic stirrer. An external HPLC pump delivered a continuous flow of aqueous medium to the flow-through cell during dissolution testing. A reversed phase high-performance liquid chromatography system using diode array detection (RP-HPLC-DAD) was coupled online to the new equipment. The injections from the miniaturized rotating disk outlet into the quantifying HPLC system were controlled by a six-position switching valve. The injection volumes from the valve and the autosampler, used for the external standards, were statistically evaluated to match each other volumetrically. No analyses were longer than three minutes, using isocratic mode. A traditional USP rotating disk apparatus was used as a reference system and the two instruments were shown to be statistically dissimilar in the numerical dissolution rate values probably due to different hydrodynamics, but had approximately the same precision/repeatability. When correlating the logarithmic values of the in vitro dissolution rate (G) with the apparent solubility (S), using shake-flask methodology in the solubility studies, the two apparatuses gave the same correlation patterns. Further correlation studies were done where the media components were altered by the use of different buffer species or additives into the buffers, such as inorganic salts. Chemometric tools, e.g. orthogonal partial least squares (OPLS), were used to better evaluate the most influential factors for G and S in different media. The most significant factor for a model basic drug substance (terfenadine) was pH, followed by the ionic strength (I) and added sodium chloride in one of the media. However, the surfactants in the Fasted State Simulated Intestinal Fluid (FaSSIF-V2) were found to be insignificant for G and S in this study (using a 95% confidence interval). The new miniaturized apparatus is a promising prototype for in vitro dissolution rate measurements both for early screening purposes and in dissolution testing during drug development, but needs further instrumental improvements.