Developing robust particle sizing methods

Particle size and particle size distribution are widely recognised as having a significant influence on the behaviour of pharmaceutical ingredients, from the solubility and bioavailability of an active through to the processability and stability of a finished blend. These correlations mean that particle size and particle size distribution are routinely identified as critical quality attributes (CQAs) – characteristics that have a defining influence on clinical efficacy. As a result, pharmaceutical manufacturers often seek to manipulate and control particle size, especially of the active ingredient (API).

ICH guideline Q6A provides a useful decision tree to help determine if a particle size specification is necessary. This guideline suggests that for both solid dosage forms and liquids containing undissolved active ingredients (i.e. drug product suspensions), a specification is required when particle size is critical to any of the following: dissolution, solubility or bioavailability; processability; stability; or product content uniformity.

Laser diffraction is a technique routinely used to meet the resulting need for particle size data, right across the pharmaceutical lifecycle. In a laser diffraction particle size analyser, the particles in a sample are illuminated by a collimated laser beam. The particles scatter the light over a range of angles, with large particles predominantly scattering light with high intensity at narrow angles, and smaller particles producing lower intensity signals over a much wider range of angles. Laser diffraction systems measure the intensity of light scattered by the particles as a function of angle and wavelength. By applying an appropriate light scattering model, such as Mie theory, particle size distribution is calculated directly from the measured scattered light pattern.