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

Dry dispersion

Energy to disperse a dry sample is applied by entraining the powder in a compressed air stream. Similar to wet dispersion, the goal is to disperse to an application-relevant degree but no further; air pressure is the lever used to control energy input. ISO 13320:2009 notes that a "pressure/particle-size" titration should in the ideal case identify a region where particle size is nearly constant over a range of pressures, indicating that agglomerate dispersion has occurred without particle breakup. However, it makes clear that this is seldom observed, in which case it becomes important to reference dry results against wet measurements, to avoid breakup and/or milling of the primary particles.


Figure 4: Method-development data for a fragile powder sample, (a) a pressure/particle-size titration, (b) a comparison of wet-dispersion data with dry results measured at a dispersion pressure of 0.2 bar.
Figure 4 (a) shows a pressure/particle-size titration for a relatively fragile material. Particle size decreases quite steeply as pressure is increased from 0 to 1 bar, but there is no way of telling simply by looking at this plot if this size reduction is the result of agglomerate breakup or the milling of primary particles. Figure 4 (b) shows that close agreement between wet results and dry data is achieved at a dispersion pressure of 0.2 bar, suggesting that pressures above this result in particle milling. As with wet dispersion, images of the particles can be useful in elucidating the effect of entrainment at different air pressures.


Figure 5: Method-development data for a pharmaceutical powder, (left) a pressure/particle-size titration, (right) a comparison of wet-dispersion data with dry results measured at a dispersion pressure of 3 bar.
Figures 5 (a) and (b) show strictly analogous data for a different material—a pharmaceutical powder. Here too, the pressure/particle size titration fails to plateau, giving an unclear indication of optimal air pressure. A comparison of data measured at 3 bar with those from a wet dispersion suggests that dispersion is inadequate—there are larger quantities of material toward the coarse end of the particle-size distribution. The dry results also show, however, a larger proportion of fines. Here then, dispersion and breakup occur simultaneously, rather than sequentially, making dry dispersion problematic. Further increasing the dispersion pressure will reduce the amount of agglomerated material present but will also increase particle damage. For this system, wet dispersion is a better option.

Measurement

The actual process of sample measurement involves recording the scattering pattern produced as the sample passes through the path of the laser. An initial background measurement captures scattering from the cell windows, any contaminant present and, in the case of wet measurement, the pure dispersant. This process assesses cleanliness and allows precise capture of the scattering pattern relating solely to the sample.

With a dry measurement, duration is set to ensure analysis of the entire sample to avoid analyzing an unrepresentative subsample. Obscuration limits can be set to prevent measurement when the powder density is too low to give a reliable signal-to-noise ratio, or, conversely so high that multiple scattering is likely.


Figure 6: Results of tracking Dv90 and measurement variability as a function of measurement duration.
For a wet dispersion, measurement duration can be specified to analyze just a small fraction of the sample, or, at the other extreme, to repeatedly measure the same sample, because material being measured can be recirculated through the measurement cell many times. Excessively long measurement times are inefficient but an overly short measurement time may give unrepresentative data, especially if the sample contains coarser particles and/or the distribution is broad, as illustrated by Figure 6. For this sample, the poor repeatability and smaller particle size recorded at low measurement times are attributable to insufficient sampling of the large particles, an issue resolved by extending measurement duration.


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