Ingredients, Formulations & Finishing Powder-mixing is a crucial process in the manufacture of tablets and capsules, which make up 80 per cent of pharmaceutical products. The blending of powders is also crucial in the production of most other types of pharmaceuticals including aerosols, suspensions and topical products. However, little technological progress has been made in this important area of pharmaceutical manufacturing. The V-blender is the equipment most commonly used to mix pharmaceutical powders; this induces mixing by the tumbling motion of particles. Yet there is little fundamental understanding of the technology, and there is no generally accepted method for altering the different operational parameters of the mixer (see (1) for detail on scaling of V-blenders). Due to this poor understanding, current mixing technology is designed empirically. It is incapable of mixing drugs of different formulations and concentrations in bulk, leaving a reduced therapeutic dosage range available to the physician (see (2) for detail on current mixing technology). A primary goal for the pharmaceutical industry is to produce a uniform product – and yet current mixing technology is capable of enormous diversity of behaviour. Within a V-blender, entirely unexpected and dramatic segregation phenomena can occur under relatively common processing conditions (see (2) for detail on V- blender behaviour). The methods traditionally used to manufacture drugs are therefore in need of revision. As drugs are becoming more potent and dosages are becoming smaller, it will become increasingly important for manufacturers to be able to understand and control blending and product properties. In particular, they will need to be able to mix smaller proportions of minute particles with other ingredients (see (2) for detail on future pharmaceutical manufacturing) but available instruments are generally too over-sized to cope with these small amounts of material. A team of chemists from Imperial College London may have found a solution to this problem. They have developed a novel powder-mixing device that could potentially provide a better-controlled system for the mixing of pharmaceutical powders in large-scale production processes. It could offer significant benefits to the pharmaceutical industry by providing opportunities for efficient, reliable and rapid development of new products. A reduction in the time-to-market of products would maximise profitability for companies and enable important therapies to be made available earlier to patients. The innovative device is a micro-scale ‘powder-mixing chip’, which can deliver specified amounts of powders more precisely and therefore offer more accurate dosing. It mixes powders by using multiple streams of nitrogen gas and sonic transducers to manipulate powder through micro-channels. A second-generation prototype chip has been built, and testing of the technology has been carried out with promising results – showing for the first time the application of miniaturised powder mixing. DESIGN OF THE ‘POWDER-MIXING CHIP’ The unique design of the chip (see Figure 1) was created using the microfabrication technique of wet etching on a glass plate. The bottom plate of the chip was etched with micro-channels, each splitting into two channels of a smaller width. This bifurcation was repeated eight times to produce eight rows of channels with an identical cross- section. In total, 256 gas channels were made leading to a main powder-moving channel. The etching was combined with the aligned placement of three further glass plates that fit exactly on top of the micro-channels, leaving the main powder-moving channel open. Another square glass plate the same size as the bottom one formed the top plate of the chip. The powders to be mixed were gravity-fed into the chip via two powder inlets, and the powder streams were conveyed through the chip by a stream of nitrogen at approximately 1.5 bar (see Figure 2). The gas microchannels prevent the powder from sticking to the walls or clogging. As the two powder streams converge in the main channel, mixing is caused by the pattern of opposing nitrogen inlets, which create turbulence. A micro-scale ‘powder-mixing chip’ has been developed that could offer potential advantages over existing mixing technologies in terms of control of product properties and process attributes, and acceleration of the mixing process. 74 Innovations in Pharmaceutical Technology Powder-Mixing on a Microchip By Michelle Cotterill at Imperial Innovations Figure 1: The ‘powder- mixing chip’ design Left: The chip design shows the gas channels (black) and the T-shaped powder-moving channel; the arrows illustrate the flow direction. Right: Shown is a small part of the chip design, where the different rows of gas channels are recognisable. Figure 2: A prototype ‘powder-mixing chip’ The figure shows a prototype with two powder inlets (fitted pipette tips) as well as three nitrogen inlets (plastic tubes connected to N2-bottle). IPT 27 2008 4/12/08 11:09 Page 74
