Reliable detection of fine particles in blends: how Mastersizer ensures accurate quality control

Introduction

Laser diffraction is widely recognized as a robust technique for particle size analysis, offering rapid, reproducible measurements across a broad size range. Because it reports size distributions on a volume-weighted basis, it is more sensitive to coarse particles than to fines. This can lead to concerns when monitoring small changes in fine particle content within a blend.

In many applications, the fine fraction plays a critical role in properties such as flowability, compressibility, and reactions like dissolution. Detecting and quantifying changes in fines, even at very low concentrations, is essential for ensuring blend uniformity and product performance.

This application note demonstrates that the Mastersizer can reliably track changes in fine particle fraction from as little as 1% fines, challenging the misconception that laser diffraction lacks sensitivity to fines.

Background

Laser diffraction measures particle size by illuminating dispersed particles with a laser beam and measuring the intensity of scattered light over a range of different angles. The particle size distribution is then calculated using an optical model, such as Mie theory, which turns that scattering data into a volume-weighted particle size distribution.

Volume weighting means that larger particles contribute more to the reported size distribution than smaller ones. While this is advantageous for many applications, it raises questions about the ability to detect small amounts of fines in a predominantly coarse blend.

Following the blending process

To evaluate sensitivity to fines, blends were prepared using lactose samples with two different particle size distributions:

• Coarse fraction: Material with a median size of approximately 160 µm.
• Fine fraction: Material with a median size of approximately 6 µm.

Blends were created with fine particle content ranging from 1% to 50% by weight. Measurements were performed using the Mastersizer with the Aero S dry dispersion unit.

Results

Figure 1: Cumulative size distributions of blends

Figure 1 shows the cumulative particle size distributions for blends containing increasing fine fractions. Even at 1% fines, the Mastersizer detects a subtle but measurable shift towards smaller sizes.

Figure 2: D[3,2], D[4,3] and Dv90 plotted against the percentage fine fraction

Figure 2 illustrates how different derived parameters can be used to track the fine particle fraction across the range of the blending process. The D[3,2] is the surface area weighted average and is most sensitive to the addition of small amounts of the fine fraction. The D[4,3] is the volume-weighted average and provides a more linear response across the whole blending range. And by comparison, the Dv90, the size below which there is 90% of the volume of the sample, is relatively insensitive to the fine particle fraction.

For pharmaceutical applications, it is worth considering how the method would be validated for use in routine QC. Guidance in the US Pharmacopeia for validating physical properties states that the linearity of the response of the technique should be tested. In this case, that’s the response of the size distribution being linear to changes in the fine particle fraction in the blend.

In this example, the fine fraction is below 30µm, so the percentage volume of material below 30µm should be a good measure of the fine fraction. Figure 3 shows the volume percentage below 30µm vs the percentage of fine material added, with the addition of a linear regression showing that the laser diffraction can accurately track the fine fraction across the range of blends.

Figure 3: % volume below 30um vs percentage fine material

Discussion

Even though laser diffraction is a volume-weighted technique, the Mastersizer is still sensitive to small changes in the fine-particle fraction. Even at 1%, the fine particle fraction can be detected, whilst retaining a linear response across the whole blending range.

This capability is critical for effectively monitoring blend uniformity in the manufacturing process and providing a reliable metric for QC.

Conclusion

The Mastersizer laser diffraction system provides reliable detection of fine particle fraction changes from as low as 1%, and provides a linear response across the blending range. dispelling the myth that laser diffraction cannot monitor fines effectively. This sensitivity ensures robust control of particle size distributions in complex blends, supporting consistent product performance and regulatory compliance.