Micrometer-scale particle sizing by laser diffraction: Critical impact of the imaginary component of refractive index

Purpose. This study evaluated the effect of the imaginary component of the refractive index on laser diffraction particle size data for pharmaceutical samples. Methods. Excipient particles 1 - 5 mu m in diameter ( irregular morphology) were measured by laser diffraction. Optical parameters were obtained and verified based on comparison of calculated vs. actual particle volume fraction. Results. Inappropriate imaginary components of the refractive index can lead to inaccurate results, including false peaks in the size distribution. For laser diffraction measurements, obtaining appropriate or "effective" imaginary components of the refractive index was not always straightforward. When the recommended criteria such as the concentration match and the fit of the scattering data gave similar results for very different calculated size distributions, a supplemental technique, microscopy with image analysis, was used to decide between the alternatives. Use of effective optical parameters produced a good match between laser diffraction data and microscopy/ image analysis data. Conclusions. The imaginary component of the refractive index can have a major impact on particle size results calculated from laser diffraction data. When performed properly, laser diffraction and microscopy with image analysis can yield comparable results.