Under pressure

Micronisation exploitation responds to R&D pressures

Research and development has always been at the centre of pharmaceuticals – by definition it is an industry driven by R&D. Traditionally, 30% of pharmaceutical sales revenues in the UK have been invested in R&D, which equates to about £3 billion, or almost £10m a day.

Such a rate of investment in product development has shown an increasing trend, with UK R&D spending having significantly increased over the last decade but at the same time, the number of new products that have been introduced has declined.

All this is set against a background of the increased speed required for getting pharmaceutical products to market, which in turn, applies pressure to the systems and methodologies applied to R&D by pharmaceutical companies. To further complicate the issues, as companies implement their own drives to increase the efficiency of their internal R&D operations, there is further growth being experienced by the external R&D service sector, where there is a current estimated spend of US$10 billion.

UK Government targets R&D in spend increase
Now, there is a new driving force behind R&D investment coming from the UK government, which through its Department of Trade and Industry (DTI) has launched a new five-year programme aimed at making the UK the most attractive place in the world for scientific research.

The programme has been targeted on all industry but with specific attention on pharmaceuticals, which accounts for a quarter of UK manufacturing's research expenditure. The DTI's target is to increase R&D from its current level of 1.9% of national income to 2.5% per year by 2014. That is set against a backdrop of growing international competition in countries attracting R&D investment and sluggish growth in European markets, compared with the low cost base for manufacturing and research in such rapidly growing regions as Asia.

Technological development within R&D has largely focused on the area of IT, which has provided the industry with fast, effective and more sophisticated ways of producing and processing R&D data throughout every stage of the product research and development cycle.

But there have been some fundamental areas where technology has limited the effectiveness of certain processes that are crucial to R&D. One of those being the batch sizes required for the first stages of product development with materials such as fine powders, which are often limited in volume at that stage.

And, according to one UK company supplying pharmaceutical product developers, dealing in batch sizes of 5g (as claimed by some companies as being effective) would probably not be good enough in the more demanding development environment that is emerging.

One of the UK’s leading suppliers of equipment to the pharmaceutical sector, Isopak, said it is specifically targeting the pharmaceutical sector with new equipment that is claimed to micronise extremely small batches of powder. It believes this will also allow much more experimentation in UK and Irish pharmaceutical laboratories than has been the case in the past.

The equipment takes what is now the well-known principle of spiral jet mills and applies it to the superfine grinding of a wide range of specialist materials where other forms of grinders are unsuitable. That is particularly apt for pharmaceuticals, where the original feed material is already fine, often soft and where a high purity of products without contamination is essential.

Spiral jet mills principles
Low capital cost spiral jet mills offer a variety of advantages compared to other mixed air jet-mechanical technologies combining air jets with mechanical classification. The spiral mills have an absence of moving parts, therefore avoiding heat generation, and have an absence of friction and so require no lubrication.
They produce a clean micronisation effect generated by laminar air jet stream (without turbulences) and mills are generally light-weighted and easy-to-assemble-disassemble without special tools and are easy-to-clean with virtually no maintenance required. They typically provide for short turn-around times and their limited contact surfaces provide very narrow particle size distribution to facilitate high productivity with 99.5% production yields claimed by one jet mills manufacturer, the Italian company Food Pharma Systems (FPS).

A common feature of jet mills is that they have a single collecting point that allows for dimensional homogeneity and have low process gas and electrical consumption rates. The system works with pressured gas (normally air or nitrogen) from 3barg (or less) up to 12barg. Piping can be flexible food grade plastic or in stainless steel, whilst valves can be of several types from manual ball valves to fully automated membrane valves, or other types. The micronisation system can be fully closed and EEx (10 bar resistant).

Air micronisers, or spiral flow jet mills, are appropriate for the ultrafine grinding of such materials, creating materials that range from 1-20 microns. Opposed jet mills can provide superfine size reduction in the 1-80 micron range, by combining the principles of opposed jet fluid energy milling with the well proven and controllable aerosplit classifier within a single unit. That technique enables accurate and controllable product sizes to be achieved with sharp cut off and a narrow size distribution.

It is an effective methodology. Product is fed into the grinding chamber by either a feed screw or a pneumatic conveying system via a rotary feeder valve.

Impact by the high speed grinding media causes the product to fracture and be thrown to the wall of the grinding chamber by centrifugal force. That, in turn, causes the product to fracture even further. Fractured particles are entrained in the induced airflow liberating around the periphery of the rotor disc, which spirals upwards around the outside wall of the internal baffle assembly (itself containing air baffles to help laminate the airflow).

The laminar airflow and particles pass to the internal classifier, which rotates in the same direction as the rotor disc. Oversized particles rejected by the centrifugal force applied by the classifying wheel are thrown to the inner wall of the baffle and then move down by gravity and by the pressure created by the classifier. The oversized particles then re-entrain in to the grinding chamber where further fracture can occur.

That recycle action continues until all the particles pass through the classifier wheel. Product being emitted from the classifier is conveyed in the process airstream where it is either collected in a cyclone or enhanced by further classification in a cyclonic classifier.

Lowering batch size thresholds to increase research
Because the first stages of product development are characterised by very limited amounts of material - starting from 200mg - Isopak believes that there is increasing emphasis on the use of very special equipment designed and developed via a miniaturisation process.

That led to a further refinement of the jet mills principle with new equipment – the LaboMill - that is now being brought in to the UK by FPS agent, Isopak. This new type of system is claimed to have further developed the potential of the process through a different approach to the geometry of the system. It is said to fully exploit the jet mills' principle and is able to handle batches from 0.2g up to 100g.

The LaboMill, unlike typical rectangular and octagonal spiral jet mills, has a continuous shape and has grinding nozzles that help maintain a non-turbulent motion of particles. The elimination of turbulence stops powder sticking against the chamber walls to form crusts and prevents particles from being prematurely classified in the centre of the mill. That benefit is also aided by low surface roughness within the mill - less than 0.25μm on contact parts and less than 0.80μm on non-contact parts.

The LaboMill also has a non-tangential Venturi-entry, whereby powder enters the chamber diagonally from the top, directly in to the spiral, without having blowback and allowing the mill to use 100% of the available energy, both at the Venturi-entry and at the grinding nozzles stated Isopak.

A further feature that makes it suitable for R&D laboratories is its overall size, measuring 300m x 350mm x 475mm. Despite the reduced dimensions, Isopak claim that the LaboMill's performance favourably compares with bigger jet mills and that it ensures the correct scale-up of the process.

Miniaturised feed system improves small batch reliability
To allow a precise and constant feeding of the powder into the milling chamber, FPS has miniaturised the feeding unit, the LaboFeeder, which is a single screw-dosing unit completely encased in stainless steel. It is claimed to substitute typical hand feeding of such small quantities offering a much higher reliability of the final results.

The spiral jet mill micronisation process is based on two main parameters to obtain the necessary productivity and Particle Size Distribution (PSD) - gas pressure and feed rate, the latter of which must be constant and precise to obtain reliable and scalable results. For this purpose the LaboFeeder was developed to constantly and precisely feed extremely small amounts of powder.

According to Isopak's managing director Robin Davies, the equipment answers a long-standing need for pharmaceutical R&D, whilst now providing UK laboratories with the effective means of achieving a step-change increase in the volume of research required by the new UK Government targets.

"The industry has been seeking equipment with this capability for a long time. We are really talking of extremely small batches of powder, something that will allow much more experimentation in the pharmaceutical laboratories of the UK and Ireland than has been the case in the past. It also opens up the possibility of increased research in to treatments and cures for a whole range of conditions from asthma to heart disease, for example," said Mr Davies.

By Robin Davis, managing director, Isopak.