Bigger is not better
Understanding size-reduction needs and techniques is key to effective grinding

The trend is towards small samples with smaller and more controlled particle sizes, yet which remain representative. A variety of equipment designs is available to achieve this goal in the laboratory quickly, safely and reliably.

In the analysis of solid material, the popular adage that “bigger is better” certainly does not apply. The goal is to produce particles that are sufficiently small to satisfy the requirements of the analysis, while ensuring that the final sample accurately represents the original material. The word “particles” means many things to many people, and can cover anything from sub-atomic particles through to veritable chunks of material measuring many hundreds of microns. The “particles” of interest to the analyst generally range from 1 µm to 2 mm in size.

The amount of material that needs to be processed in order to produce a representative sample will depend on the amount of material received and the largest particle or grain size present in the sample. There are various formulas that help determine the mass that should be sampled, and most of these include the parameter D3, where D is the diameter of the largest particle. The use of such formulas reduces sampling errors to acceptable levels. Reduction of particle or grain size is of utmost importance if the analyst hopes to generate samples which are both small and representative.
Materials differ widely in their composition and physical properties, and as a result, many different grinding principles can be applied. This fact, together with
other variables such as initial feed or “lump” size, fineness needed and amount of sample available, results in a wide range of equipment available to the researcher. Some grinding processes may require extra techniques or aids to help the size reduction process, without contaminating or altering the material in any way. The most common example of such an aid is cryogenic grinding, where soft material such as animal tissue or plastics will not grind unless it is made brittle through the use of dry ice or liquid nitrogen. Finally, choosing the most appropriate mill will
often require the help and support of the manufacturer. This process may include a trial sample to help finalize the decision.
Smaller particles, finer grinding
In the pharmaceutical industry the science and study of particles, including their size and shape, is very critical. Particle characteristics can affect many different areas, including inhalation delivery systems, tablet dissolution characteristics, formulation quality and solubility or absorption. As in many industries, there is a move towards smaller particle sizes and therefore an increasing need to grind
finer and finer. The following sections address specific applications that are common to the pharmaceutical industry.
Animal/human tissue
Before DNA and RNA can be extracted from mammalian tissue, the material has to be homogenized or ground. Most animal tissue, and particularly lung, liver and muscle, is soft at room temperature and is also susceptible to damage by heat naturally generated during the grinding process. It is therefore necessary to pre-chill the material in liquid nitrogen before grinding. Small bead mills are ideal for this, since the grinding vessel, complete with material and media, can be completely immersed in liquid nitrogen and the powerful grinding action will result in complete homogenization before the sample has had a chance to warm up. This method also can be applied to some of the harder tissues, such as bone or cartilage, as well as plant material.
Active ingredients
This application is most common during the drug development phase, and usually requires size reduction down to 1 µm or even below. Methods used to achieve such fineness include jet milling, which relies on very high-energy particle-to-particle collisions induced by high velocity air jets in a hollow chamber. Another technique is planetary ball milling, where the material is processed in a jar using grinding media made of the same material as the jar. In a similar manner to the solar system, the mill rotates the jar on a turntable but at the same time, the jar rotates on its own axis in the opposite direction to that of the rest of the system. This generates very high milling energy, resulting in fast reduction to very small sizes. Single micron and sub-micron sizes can be achieved through wet milling, usually in alcohol; dry milling is used when the size reduction demands are not as high. Grinding jars are available in a number of different sizes and materials, the latter being necessary to avoid contamination from heavy metals, for example, during the grinding process. The smaller bead mills mentioned above can also be used for size reduction of active ingredients. They are particularly useful when only small sample amounts are available or when the material requires pre-chilling prior to grinding.
Finished products
Pharmaceutical finished products often take the form of tablets or capsules, which bring their own sets of challenges when it comes to grinding. Classical size-reduction techniques involve methods such as grinding the tablets in a mortar, which is both time-consuming and labor-intensive. Grinding mills can do the job in a fraction of the time, produce a much more consistent sample, and free technicians for more productive tasks. The following techniques can be used for tablet grinding as well as other pharmaceutical applications:
Mixer mills are particularly suitable for the rapid and efficient grinding of tablets and capsules. Grinding takes approximately two minutes and the use of a closed jar guarantees loss-free grinding. The process is suitable for tablets of different sizes and hardnesses. Mixer mills have a capacity up to 20 cm3 of tablets.
A laboratory knife mill is an ideal choice for coated tablets, since the coating—usually made of sugar or gelatin—prevents these from being crushed in a mixer or ball mill. With a capacity of over 100 cm3, such a mill is also suitable for grinding large tablets.
Ultra-centrifugal mills have a wide range of applications. Their unique grinding action makes them suitable for grinding medium-to-large tablets when wildly varying quantities (25–5,000 cm3) are required.
The mortar mill, a mechanized version of the classic hand pestle and mortar, is well suited for tablet grinding as well as for mixing and homogenization of powders, suspensions and pastes.
Other pharmaceutical applications
There are other applications that involve the production of “particles” used in pharmaceutical and medical applications. An interesting application is the grinding of human cortical bone to produce raw materials used in various preparations for bone grafts and implants. The bone material is often first processed in tissue banks around the country, and then reprocessed by the companies who produce the final products. The process usually requires two different mills, the first of which is a cutting mill. These heavy-duty mills are designed to reduce larger pieces of bone (up to 50 mm) down to a few millimeters or less. Some of the material produced by this mill can be used without additional processing, but the remainder is then processed in an ultra-centrifugal mill. This versatile mill further reduces the bone pieces to the sizes needed for their intended use. Both mills have designs that make cleaning easy, and include many safety features to protect the users from possible injury.
Conclusions: The analytical world is getting smaller, both figuratively and literally. The importance of the pharmaceutical industry in particle technology cannot be overstated and, directly and indirectly, it has been responsible for many of the advances that have occurred during the past few years. In size reduction technology, there is a trend towards smaller samples with smaller and more controlled particle sizes, which yet remain representative of the material being analyzed. Companies must offer a selection of size reduction equipment and accessories that can meet these demands.