(93a) Micronization of Pharmaceutical Powders by High Pressure Homogenization in Compressed Fluid Antisolvents

Controlled comminution of solid materials to the micron and submicron range is of increasing interest for the pharmaceutical industry, and product uniformity with respect to size, shape, and morphology is a key parameter to compare or select processes for robust industrial scale operation. Applications for micro- and nanoparticles range from bioavailability enhancement by size reduction, to improved release from composite formulations by dispersing drug micro- and nanoparticles in suitable carriers, and targeted deposition of inhalation drugs in the respiratory tract, among others. While conventional precipitation or phase separation methods hardly ever match required product PSDs in single step operation, standard wet and dry milling processes are often associated to poor PSD control, equipment clogging, or product contamination. The latter, along with the frequently reported increase of the amorphous content upon comminution, is particularly critical in pharmaceutical applications. High pressure homogenization (HPH) has recently been reported to overcome these most severe drawbacks of conventional processing, but its operation in a liquid non-solvent requires extensive post-processing to isolate the dry product, e.g. through filtration, drying, and subsequent de-agglomeration, or through spray or freeze drying. Not surprisingly, product quality is often adversely affected during post-processing. In this study, we propose to suspend coarse solid particles for homogenization in compressed fluid non-solvents such as carbon dioxide, or pharmaceutical propellants HFA227 and HFA134a. Once micronization or nano-sizing is complete, dry powders are obtained directly from the proposed process upon depressurization, thus eliminating any additional downstream processing. Phenytoin is used as a model drug along with a number of proprietary pharmaceutical compounds, and the effect of characteristic process parameters such as relaxation pressure, initial solid content, viscosity, or number of passes through the unit on product quality is assessed experimentally. Product quality is characterized in terms of particle size and shape, PSD, morphology and purity, and critically compared to liquid phase operation. The assessment of pharmaceutical performance is also shown for selected applications. Conventional liquid based HPH is good for micronized suspension whereas compressed gas HPH provides dry powder formulations.