Micronisation of Pharmaceuticals Using Dense Gas Based Microfluidic Processes

Micro-structured devices have attracted increasing interest in intensifying manufacturing processes in recent years. In fact, various miniaturized and micro-devices have been used for continuous production of pharmaceuticals, nanomaterials and organic compounds, and multiple functions of chemical analysis, for instance, the paper-based analytical devices (μPADs). However, these tools were only very recently made compatible for high pressure or high temperature processes. Supercritical fluids (SCFs) find useful application in performing green chemistry and engineering, especially in pharmaceutical industry. The concern for sustainable environment was the main impetus for using SCFs. The unique properties of some SCFs have enabled the possibility of replacing toxic organic solvents. In this study, the hypothesis that dense gas based microfluidic processes can be developed as an intensified and effective technique to micronize drug particles was tested using two poorly water-soluble pharmaceuticals: copper indomethacin and budesonide. Carbon dioxide was used as an antisolvent to conduct precipitation of the drugs within a microfluidic system under supercritical conditions. The experiments were designed with the aim to optimize the process; the effects of operating parameters, namely temperature, pressure, flow rates of drug solution and carbon dioxide were manipulated to reduce particle size and improve product yield. The Taguchi Method (TM) and Response Surface Methodology (RSM) were introduced to improve operating conditions and run statistical analysis. In the study of synthesis and micronisation of copper indomethacin, particles of diameter less than 5μm were produced at a yield of 80% and the purity of the product was upwards of 95%. The results from the particle size distribution analysis indicated that 90% of the product consisted of particles that were less than 8μm in diameter. The statistical analysis results also demonstrated that temperature and pressure were two significant factors affecting product yield while the flow rates of carbon dioxide and solution had minor impact. To extend the application of microfluidic processes, budesonide was processed in a dense gas assisted microfluidic system. The experiments were conducted under the optimal conditions computed by the Taguchi Method; a yield of budesonide particles of 71.1% was achieved. A particle size distribution study showed that 10% by volume of precipitate produced had diameter smaller than 4μm, and 90% of them having diameters under 10μm. Working under the dense gas or supercritical conditions at micro-scale combines the advantage of size reduction provided by micro-devices to the unique properties of the dense gas or supercritical fluids. Therefore, a dense gas based microfluidic process addresses the limitations of both macro-scale supercritical fluids reactors and conventional liquid microfluidic systems, and brings benefits to particle engineering