Method Development for Laser-Diffraction Particle-Size Analysis - Pharmaceutical Technology

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Method Development for Laser-Diffraction Particle-Size Analysis
The author examines the process of method development, with reference to ISO 13320:2009 and relevant monographs from the United States and European pharmacopoeias.


Pharmaceutical Technology
pp. 100-106

Method validation

When assessing the validity of measured results and determining whether a defined procedure and associated system are fit for purpose, two concepts are central: repeatability and reproducibility. Assessing repeatability involves duplicate measurements of the same sample. It therefore tests the precision of the instrument and the consistency of the sample. Reproducibility is a broader concept that also encompasses sampling from the bulk.

One aspect of repeatability is the performance of the analyzer. ISO13320 (2009) provides revised accuracy acceptance criteria for performance verification, which typically involves measurement of an appropriate standard. Because laser diffraction is a volume-based measurement technique, sampling errors for large particles will cause greater uncertainty in the Dv90 than in the Dv10. The revised acceptance criteria for reference materials reflect this and are:

  • +/– 3% for Dv10 (and all other value of cumulative undersize distribution between the 10th and 30th percentiles)
  • +/– 2.5% for Dv50 (and all other value of cumulative undersize distribution between the 30th and 70th percentiles)
  • +/– 4% for Dv90 (and all other value of cumulative undersize distribution between the 70th and 90th percentiles).




To test repeatability for a given application, duplicate measurements of the same sample are performed. The precision of laser diffraction measurements is usually assessed using the term coefficient of variation (%COV) which is defined according to the following equation (1):

ISO 13320:2009 states that repeatability tests should show a %COV of less than 3% on Dv50 and below 5% for Dv10 and Dv90 but indicates that these values can be doubled for samples containing particles smaller than 10 μm, because of the difficulties of dispersion. In ideal conditions, however, much better performance is readily achievable: a %COV of less than 0.5% for samples larger than 1 μm and below 1% for samples finer than this, is realistic.

Reproducibility is assessed by measuring several samples from the same batch of material and therefore tests how representative the sampling procedure is. Both USP and the European Pharmacopoeia recommend acceptance criteria for reproducibility testing of a %COV of less than 10% on Dv50 or any similar central value and less than 15% on values toward the edge of the distribution such as Dv10 and Dv90 (2, 6). Once again, these limits are doubled for samples containing particles smaller than 10 μm.

Conclusion

The highly valued simplicity of routine laser-diffraction measurement belies the relative complexity of method development. During the last decade, considerable progress has been made toward securing a comprehensive understanding of how best to define measurement methods for laser-diffraction analysis and implement them. The new ISO standard and relevant chapters of the USP and the European Pharmacopoeia provide useful summaries of the significant guidance now in place. Instrument manufacturers recognize that helping users to access all available information—through education, direct support and smarter software—is the way to maximize the benefits of this vital analytical technique.

Anne Virden is a product technical specialist in diffraction at Malvern Instruments, Enigma Business Park, Grovewood Road, Malvern, Worcestershire, WR14 1XZ, UK, tel. +44 (0)1684 892456, fax + 44 (0)1684 892789,
.


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