Laser diffraction (low-angle laser light scattering) is one of the most widely used techniques for particle size analysis in the pharmaceutical industry. It determines the particle size distribution of a sample by measuring the angular variation in the intensity of light scattered as a laser beam passes through a dispersed particulate sample—either in liquid suspension or dry powder form.

Sample Preparation for Laser Diffraction

Depending on the type of measurement to be performed and the instrument used, particles can be presented to the instrument dispersed in either a liquid or a gas. Adequate dispersion is required to ensure aggregates of particles are dispersed into primary particles if that is the purpose of the assay.

For particles dispersed in liquid, a dispersing agent (e.g. a surfactant) and/or mechanical agitation may be required. Dry powders may be dispersed with use of compressed gas at a pressure sufficient to ensure adequate dispersion, without causing undue attrition and consequent size reduction.

The Principle of Laser Diffraction Method

Monochromatic light from a helium–neon laser is incident on the sample of particles, dispersed at the appropriate concentration in a liquid or gas, and diffraction occurs. The scattered light pattern is focused by a Fourier lens directly onto a photodetector, comprising a series of detectors.

The light flux signals occurring on the photodetector are converted into electric current, which is digitized and processed into size-distribution data, based on an optical model using the principles of Fraunhofer diffraction or Mie theory. The measured scattering of the population of particles is taken to be the sum of the scattering of the individual particles within that sample.

Fraunhofer diffraction and Mie theory

For particles that are much larger than the wavelength of light, any interaction with particles causes light to be scattered in a forward direction with only a small change in angle. This phenomenon is known as Fraunhofer diffraction and produces light intensity patterns that occur at regular angular intervals, with the angle of scatter inversely proportional to the diameter of the particle producing it.

The composite diffraction pattern produced by different-diameter particles may be considered to be the sum of all the individual patterns produced by each particle in the size distribution, at low to medium particle concentrations. The Fraunhofer model was used in early instruments and has the advantage that the refractive indices of samples and the dispersing medium do not need to be known, i.e. the model assumes particles are opaque and transmit no light.

As the size of particles approaches the dimension of the wavelength of the light, some light is still scattered in the forward direction, according to Mie scatter theory, but there is also some side scatter at different wavelengths and polarizations. Use of the Mie theory requires consideration of the optical properties of the dispersed particles and the dispersion medium, i.e. knowledge of their respective refractive indices is required for calculation of particle size distributions, but is superior for accurate determination of size distributions of smaller particles.

Reference:

• Aulton, M. (2018). Aulton’s pharmaceutics, the design and manufacture of medicines. Edinburgh. : Elsevier