Particle size analysis

Apr 01, 2009
Volume 21, Issue 4

The ideal technique will report data that correlate closely with a given performance attribute. Measured parameter is one aspect of this, but the basis for the distribution is also important. With a number-based particle size distribution, the number of particles in each size range is reported; with a volume-based distribution, it is the volume, or for particles of constant density, the mass of material. In the case of pharmaceutical products, a mass or volumeweighted distribution is often the most relevant descriptor of the content of active ingredient as a function of particle size.2 Volumebased methods may be more sensitive to the presence of larger particles and aid the detection of the end point for unit processes, such as milling. However, number-based methods may improve detection of small amounts of fine particles, which may impact properties such as powder flowability and dissolution rate. Therefore, the choice of technique depends on the application.

More pragmatic issues include the speed of measurement and how easy it is to transfer the technique from the laboratory to the manufacturing floor. During the early stages of a development, longer analytical times may be acceptable, particularly if the results are information rich. For particle characterization, image analysis can be an excellent choice because it provides statistically relevant size and shape data as well as visual images, which in combination give detailed insight into the product. Measurement times are relatively long (approximately 15–20 min), but still much shorter than using manual microscopy.

In contrast, PAT must offer much more rapid analysis because the aim is measurement of a dynamic process. Where extremely fast analysis is required, other techniques become more valuable. Laser diffraction, for instance, provides a complete volumebased distribution in milliseconds. This makes it extremely productive for particle characterization in the laboratory and equally valuable for the realtime monitoring of processes, including spray events.

Whatever the analytical method, many of the issues regarding instrument choice are shared — ease of use, flexibility and reproducibility are all key. For laser diffraction, decades of development have streamlined analytical methods; the best instruments now offer fully automated operation driven by standard operating procedures (SOPs). The repeatability of such systems is exceptionally high. Advances in the core technology have also delivered improvements in fundamental performance, broadening measurement ranges. A single instrument can be used for many different samples, building greater value into the investment.

How do I develop and validate a methodology for particle size analysis?

If a particle size specification is required, then so too is an analytical method that will accurately reflect whether or not a material meets the specification. Measurement should be repeatable, reproducible and robust.

Figure 2
If a method is highly repeatable it means that running the same sample on the same instrument produces very similar results. Repeatability is determined by instrument performance and the state of dispersion of the sample. Typically, the aim is primary particle size measurement, in which case it is necessary to disperse any agglomerates/aggregates prior to analysis. Research has shown that inadequate dispersion is the greatest source of measurement error for particles with a diameter of 20 μm or less (Figure 2).3

Laser diffraction can be used for either wet or dry analysis. Wet sample dispersion involves the use of a suitable dispersant to separate the particles, followed by stabilization with admixtures or surfactants to prevent recombination of the particles during measurement. Vigorous stirring or ultrasound treatment promotes initial dispersion. With a dry system, the air pressure used to draw the sample into the measurement zone can be manipulated to control the degree of dispersion.

A wellengineered instrument will produce repeatable measurements provided dispersing conditions are appropriate and well defined, and the concentration of particles in the measurement zone is suitable. However, reproducible measurement is a more exacting requirement. A highly reproducible procedure gives accurate and precise results for different samples, so sampling methodology is a contributory factor. The US and European pharmacopoeias specify a target reproducibility of 10% for the volume median diameter (Dv(50)) for particles >10 μm in diameter and 20% for those that are smaller.4,5 This figure takes into account all the errors associated with the entire analytical process.

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