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

Sample preparation

Laser diffraction is suitable for the analysis of a wide array of sample types, but it is essential to appropriately tailor the sample-preparation method. For sprays, aerosols, and gas bubbles in solution, USP <429> strongly discourages sample preparation, or indeed sampling, because of the difficulty of imposing either step without skewing the measured particle-size distribution. Laser diffraction instruments designed specifically for the analysis of sprays have much to offer here, being able to measure relatively concentrated sprays directly.

For other sample types, there is a choice to be made between wet and dry dispersion. Influencing factors include the natural state of the sample, the ease with which it can be dispersed and the volume of sample to be measured. Where the sample is dry powder, dry dispersion may present the simplest option, but there are several reasons why wet measurement may be preferred. These include:

  • Cohesivity—cohesive and or very fine particles (below 20 μm) can be difficult to disperse completely using dry techniques
  • Toxicity—handling samples in the wet state makes control easier, reducing the risk of inadvertent inhalation
  • Friability—wet dispersion can provide more gentle dispersion for fragile particles.

Because wet dispersion is appropriate for so many samples, it is the method most widely used for laser diffraction measurement.

A further issue to consider alongside the choice of dispersion method is: What should be the goal of the dispersion procedure? While it is the primary particle size of an active ingredient for a tablet blend that will influence its in vivo dissolution and consequent bioavailability, for instance, in other applications, the particle size of agglomerates may be more relevant. A good example of this is the study of suspension stability where, if particles are prone to agglomeration, it is agglomerate size that will control sedimentation rates.

Wet dispersion

Factors to address in the development of a robust wet dispersion include dispersant choice, conditions for stable dispersion, and sample concentration. The aim is to reliably produce a stable, representative dispersion of suitable concentration for measurement.

Table I: Dispersants in order of polarity.
Dispersant choice. The dispersants used in laser-diffraction measurement range from highly polar water to very nonpolar long-chain alkanes and alkenes (see Table I). A candidate dispersant should:
  • Be transparent to the wavelength of light used in the measurement
  • Be chemically compatible with the materials used in the instrument
  • Not dissolve the particles
  • Be free from bubbles and other particles
  • Favor easy and stable particle dispersion
  • Have a refractive index different to that of the particles
  • Have suitable viscosity.

The dispersant must also be able to wet the sample. Wetting can be assessed by mixing sample and dispersant in a beaker and observing the resulting suspension. A uniform suspension is indicative of good wetting; sedimentation of the sample on the base of the beaker is undesirable. Wetting depends on the surface tension between the particles and dispersant and can, therefore, be modified through the use of surfactants. Other admixtures may also be beneficial, with the pH of the dispersant an important variable for systems having an iso-electric point (4). ISO 14887 is a useful source of further guidance for the dispersion of powders in liquids (5).


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