A glimpse into the miniature world

Whether perfecting a blend of cement or researching new protein therapies, success in the lab will often hinge on understanding the size, shape or interaction of very small particles.

One of the greatest challenges for researchers can be selecting from the wide range of instruments and techniques for studying them.

There is no one-size-fits-all solution that dominates the field, says Paul Kippax, leader of the advanced materials group at Malvern Instruments.

This means characterisation techniques are often narrowed down on the basis of the size of the material under investigation.

Starting at the smallest end of the scale, the size of particles can often be determined from the way they scatter light. Techniques like Dynamic Light Scattering (DLS) are widely applied for characterising nanomaterials, says Kippax.

For larger particle sizes – 10nm to 3.5mm – laser diffraction is increasingly being employed as a fast and robust alternative to traditional methods such as sieving.

And for those looking to measure particle size and shape between 500nm and several millimeters, image analysis is often the preferred technique.

Choice of technique may also be determined by the amount of information required, and how critical this is to the success or failure of a new process or material.

For example, in pharmaceutical tablet formulations, particle size is measured in order to predict the rate of solubility, and therefore drug bioavailability, Kippax says.

However, size and shape information may provide additional information to aid processability assessments, enabling improved control of content uniformity, for example.

Blended solutions
And as the number of generic products made by the pharmaceutical industry has increased, he has also observed a growing interest in component-specific particle size measurements within blends.

“This is important in the pharmaceutical industry, where the particle size of the active pharmaceutical ingredient within a formulation can be the most important parameter in defining bioavailability,” Kippax adds.

On the industrial side, the rise of additive manufacturing is another discipline where technologies to understand and control particle properties are often critical to success.

Also within industry, changes in feedstock materials from new suppliers can also influence product performance. In some cases, size specifications alone are insufficient to determine whether a new material will perform well, creating an increasing demand for image analysis techniques to establish particle shape as well as their size.

To address emerging needs, Malvern Instruments has begun combining techniques to produce new instrumentation with capabilities “that add up to more than the sum of their parts for more detailed particle characterisation,” says Kippax.

The biggest issues today are software and usability, which determine how quickly and how succinctly you can turn data into something useable for the user

Brian Miller, director of Meritics

For example, the combination of imaging with spectroscopy is now making it possible to drill further into the chemical composition of individual components within a blend, says Kippax. This can offer powerful capabilities for comprehensive quality assurance and quality control (QA/QC).

While many of the existing particle analysis technologies can be traced back to the 18^th century, the most revolutionary recent addition to the particle analysis field is the computing power able to solve some of the mathematical challenges, says Brian Miller, director of Meritics.

“The biggest issues today are software and usability, which determine how quickly and how succinctly you can turn data into something useable for the user,” he says.

While the pharmaceutical industry remains one of the biggest users of particle characterisation technology, Miller says it can be applied to a vast range of applications, from cement making to protein therapy.

This has spurred development of a wide selection of sizing and characterisation techniques.

“As an independent organisation, we take a view on the best technique for our customers to measure parameters such as particle size, shape, density, porosity, surface activity,” says Miller.

“We can either hire instruments for short-term projects or run samples and characterisation services for those who don’t have the need to purchase equipment.”

Safety assurances
Health and safety regulations are also driving the popularity of some technologies, says Miller. This is especially so in the emerging field of protein therapy, where it is critical to protect people from substandard products.

Another area of interest is measurement of the shape of particles, especially when this might account for performance variations between products.

“The ability to measure and express this in a format that people can understand is something that may become more desirable – especially if you could do that in the submicron range without the need for an electron microscope,” says Miller.

Another exciting area of development is the convergence of age-old microscopy with flow imaging to observe particles in real time, says Kent Peterson, chief executive of Fluid Imaging Technologies.

People have been doing particle analysis for 100 years, says Peterson, largely through microscopy.

“Laser diffraction will find and count particles and give a ballpark size, but it won’t give you morphological information and identification. Pictures are worth a thousand words,” he says.

The company’s FlowCam particle imaging and analysis system was developed to fit this need, combining high-speed digital imaging with flow cytometry and microscopy.

While many analysers will provide a distribution of particle size, FlowCam can make over 30 different measurements for each particle, says Peterson.

Laser diffraction will find and count particles and give a ballpark size, but it won’t give you morphological information and identification. Pictures are worth a thousand words

Kent Peterson, chief executive of Fluid Imaging Technologies

This allows it to automatically detect, image and characterise thousands of individual particles and microorganisms in a matter of seconds.

For applications where particle shape is important, Peterson says FlowCam is also able to extract a variety of morphological properties from digital images of each particle.

Although it has a wide range of uses, he adds that it has particular importance for biopharmaceutical research to safeguard efficacy, safety, and immunogenicity of injectable drugs in line with evolving Food and Drug Administration (FDA) regulations in the US.

One example of this is identification of protein molecules with potential to agglomerate and produce harmful immunologic responses.

Water utilities monitoring drinking water supplies are also using the technique to identify species of toxic or odour producing algae, says Peterson.

“They may have a spring bloom of cyanobacteria that they need to be on guard for.”

Its expanding FlowCam user base includes the likes of Nestle and GlaxoSmithKline. However, Peterson says the technology is yet to gain mainstream attention.

“We are at the front edge of market penetration and awareness of flow imaging as a particle analysis alternative. But we can envisage a future where flow imaging becomes the next Xerox of microscopy,” he says.