(506a) Continuous Production of Stable Drug Nanoparticle Suspensions Via Wet Stirred Media Milling

One way to improve the bioavailability of poorly water-soluble compounds is to reduce particle size of drug crystals down to nanoscale via wet stirred media milling. To prevent aggregation of nanoparticles, polymers and surfactants are dissolved in water acting as stabilizers via adsorption onto the drug crystals. The nanoparticle suspensions can be either filtered/sterilized and packaged (oral liquid, nasal, inhalation, parenteral) or can be converted into a solid dosage forms (capsules, tablets) upon various spraying processes such as spray drying, fluidized bed spray drying or fluidized bed coating/granulation.

In the last two decades, ample experimental data were generated in the area of nanoparticle suspension production via media milling. Recirculation mode of milling operation, where the nanoparticle suspension in a holding tank continuously circulates through the stirred media mill, has been commonly used in lab, pilot, and commercial scales. Although the circulation is continuous, the recirculation operation mode is overall a batch operation, requiring significant number of batches for a large-volume pharmaceutical product. To the best knowledge of the authors, a detailed engineering analysis of the continuous wet stirred media milling of drugs does not exist in the open literature. We present a comparative analysis of recirculation mode and continuous mode by studying the wet milling of Griseofulvin as a model drug in a stirred media mill. A suitable set of operating and formulation parameters was obtained by conducting milling experiments in the recirculation mode. The knowledge generated from recirculation milling guided the experiments with continuous milling mode, where drug suspension was passed through the stirred media mill multiple times. This multi-pass continuous operation with a single mill closely mimics the operation of a number of mills in series. Impact of various processing parameters on the mean residence time and the process dynamics has been studied with the hope of optimizing the continuous milling process. Our results suggest that continuous milling of drugs in a series of few mills leads to the production of stable nanoparticle suspensions. Continuous mode can produce as small particles as recirculation mode given sufficient residence time in a mill or minimum number of mills in series.