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


Figure 1: Contrasting emulsion stability in deionized and tap water. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
When characterizing emulsions, choosing a dispersant as close as possible to the continuous phase minimizes the risk of dissolution shock, which is the modification of droplet size by the dissolution process. Figure 1 contrasts the suitability of tap and de-ionized water for dispersing an example emulsion; 10 measurements were made with each system to assess dispersion stability in each case.

With tap water, droplet size increases over time, a response attributed to flocculation. Deionized water prevents this and is therefore more suitable. These data highlight the importance of making repeat measurements to assess dispersion stability because initial measurements of particle size are almost identical, with differences becoming increasingly pronounced over time.

Optimizing conditions for stable dispersion. Energy input maintains a stable dispersion with the chosen dispersant. With wet dispersion, the sample is typically made up in a dispersion cell, which is essentially a feed vessel for the analyzer. Energy for dispersion comes from the agitator in this cell, from the pump that transfers the sample to the measurement zone, and from sonication if applied. Effective tuning of these three inputs ensures repeatable dispersion to a size appropriate to the application, avoiding primary particle breakup.

Both USP <429> and ISO 13320:2009 highlight microscopy as a useful tool for determining whether or not suitable conditions have been established. Particle imaging allows for the identification of agglomerates, and can be used to cross-validate the particle size range of the sample.


Figure 2: Optimizing conditions for stable dispersion.
Figure 2 illustrates the progression of an agglomerated sample toward stable dispersion. Images show agglomeration when only the dispersion cell stirrer and pump are active; however, when ultrasound is applied particle size reduces to a stable level. The leveling of particle size suggests that primary particles are undamaged, and the results provide an indication of required sonication time. When the ultrasound is switched off, the stable dispersion persists, and image analysis confirms the presence of discrete primary particles.

For certain types of samples, there are additional factors influencing dispersion conditions. With emulsions for example, excessively high agitation may shear emulsion droplets, in which case droplet size will decrease with increasing agitator speed. On the other hand, for samples containing coarser particles, higher agitator speeds may increase particle size by reducing the tendency to sediment. Finally, where particles have a high aspect ratio, certain agitator or pump speeds may cause flow alignment. Nonrandom alignment can affect the measured particle-size distribution, so this phenomenon should be carefully considered if samples fall into this classification.

Setting sample concentration. The ideal sample for laser-diffraction analysis is sufficiently concentrated to give a stable scattering signal but dilute enough to avoid the issue of multiple scattering. Multiple scattering occurs where the light interacts with more than one particle before being detected, and leads to an underestimation of particle size.


Figure 3: Obscuration titrations for submicron and larger particle samples.
Obscuration is a measure of the percentage of emitted laser light that is lost by scattering or absorption. It is therefore indicative of sample concentration. Carrying out an obscuration titration and plotting particle size as a function of obscuration is an efficient way of identifying a concentration range for reproducible measurement, as Figure 3 illustrates. Data are shown for two samples: one with particles in the submicron region, the other with a Dv50 of > 30 μm.

With the submicron-sized sample, particle size begins to decrease at obscurations above 5%, as multiple scattering begins to have an appreciable effect. For the sample containing larger particles, particle size is stable over a much wider obscuration range. Larger particles scatter light at relatively high intensity and narrow angles so measurement is less influenced by multiple scattering, and the signal-to-noise ratio is less of a challenge. Where larger particles are present, or the particle size distribution is particularly wide, concentration may be set on the basis of sampling requirements (as previously discussed).


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