Particle size analysis

Apr 01, 2009
Volume 21, Issue 4

Many analysts underestimate errors that arise from sampling. Laboratory analysis involves measuring a small amount of material to determine the properties of a much larger bulk. Ensuring the sample is truly representative is essential. It is estimated that for systems containing particles >75 μm in diameter, sampling is the greatest source of error.3 As with dispersion, it is sensible during method development to investigate the impact of sampling technique on size measurement and to closely define a procedure.

Comparison of different measurement techniques can provide valuable insight for method development; for example, image analysis provides size and shape data that verify effective dispersion. With dispersion, the aim is to apply sufficient energy to disperse the particles without breaking them up. Image analysis is a relatively straightforward way of determining whether or not this aim has been achieved. Comparing image analysis and laser diffraction data is also a good way of confirming that the optical properties being used for diffraction analysis are correct.

Figure 3
Validation is the final step in the development of a particle size specification and an associated measurement method. FDA guidance states that, for particle sizing, "methods validation usually involves an evaluation of intermediate precision and robustness".6 Intermediate precision is related to both repeatability and reproducibility, and is tested by measuring the same sample, on a different day, using a different instrument. Robustness is assessed by evaluating the impact of small changes to the methodology on the results.

FDA guidance also states that "assurance should be provided that the data generated are reproducible and control the product's quality".6 Effective method development, particularly when implemented through SOPs, will give reproducible analysis. For the particle specification to control product quality, it essential to have effective definition that considers the variability associated with measurement. Understanding the particle size range that gives acceptable performance boundaries for a product enables the specification to be set. The specification will be narrower than the true window of acceptability by an amount that depends on the variability of the analytical method (Figure 3). If the product meets this specification then it will deliver the required performance.

Paul Kippax is Product Manager Diffraction Systems at Malvern Instruments Ltd (UK).


1. ICH Topic Q6A — Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, December 2000.

2. D.J. Burgess et al., AAPS J., 6(3), article 20 (2004).

3. H. Merkus "Quality Assurance in Particle Size Measurement" from Improving Standards in Particle Size Distribution Measurement, Engineering Research Centre for Particle Science and Technology (Gainsville, FL, USA, February 1997).

4. General Chapter <429> (2008), "Light Diffraction Measurements of Particle Size," United States Pharmacopeia.

5. European Pharmacopoeia, Chapter 2.9.31, Laser Diffraction Measurement of Particle Size, Supplement 5.6 (2006), p 4429.

6. FDA Draft Guidance — Analytical Procedures and Methods Validation, August 2000.

7. D.J. Wheeler, How to Establish Manufacturing Specifications (2003).

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