Particle Size Distribution (PSD) Study of Pharmaceutical Materials

Particle size is a crucial parameter for the pharmaceutical materials, because it influences surface area and porosity and, hence, has an impact on bioavailability, effectiveness and shelf life of a drug.  Particle size distribution (PSD) is among the most important parameters to check the blended granules of solid dosage form. In fact, when evaluating new drugs.

• Sieving is one of the oldest methods of classifying powders and granules by particle size distribution. Mechanical sieving is most suitable where the majority (at least 80%) of the particles are larger than about 75 μm.

• Among the limitations of the sieving method are the need for an appreciable amount of sample (normally at least 25 g, depending on the density of the powder or granule, and the diameter of test sieves) and difficulty in sieving oily or other cohesive powders or granules that tend to clog the sieve openings.

• If the test specimen weight is not given in the monograph for a particular material, use a test specimen having a weight between 25and 100 g, depending on the bulk density of the material.
• Sieving should be carried out under conditions that do not cause the test sample to gain or lose moisture.

• Where only a specimen of 10 to 25 g is available, smaller diameter test sieves conforming to the same mesh specifications may be substituted, but the endpoint must be redetermined.
• The test sieving analysis is complete when the weight on any of the test sieves does not change by more than 5% or 0.1 g.

• If less than 5% of the total specimen weight is present on a given sieve, the endpoint for that sieve is increased to a weight change of not more than 20% of the previous weight on that sieve.

• If more than 50% of the total specimen weight is found on any one sieve, unless this is indicated in the monograph, the test should be repeated.

• The nest of sieves agitates for 5 minutes.

• Total losses must not exceed 5% of the weight of the original test specimen.

• The raw data must include the weight of test specimen, the total sieving time, and the precise sieving methodology and the set values for any variable parameters, in addition to the weights retained on the individual sieves and in the pan.

• Particle size testing may be performed as an in-process test, or may be performed as a release test, depending on its relevance to product performance.

• For some new drug substances intended for use in solid or suspension drug products, particle size can have a significant effect on dissolution rates, bioavailability, and /or stability.

• Optical microscopy may be used depending on the measuring purpose and the properties (morphological appearance, size and shape) of test specimen.

• The laser light diffraction technique used for the determination of particle-size distribution is based on the analysis of the diffraction pattern produced when particles are exposed to a beam of monochromatic light.

• A representative sample, dispersed at an adequate concentration in a suitable liquid or gas, is passed through a beam of monochromatic light, usually a laser. The light scattered by the particles at various angles is measured by a multi-element detector. Numerical values representing the scattering pattern are then recorded for subsequent analysis. These scattering pattern values are then transformed, using an appropriate optical model and mathematical procedure, to yield the proportion of total volume to a discrete number of size classes, forming a volumetric particle-size distribution.

• Traditionally, the measurement of particle size using laser diffraction has been limited to particles in the range of approximately 0.1μm to 3 mm.

• The particles can enter the laser beam in two positions. In the conventional case the particles enter the parallel beam before the collecting lens and within its working distance. In so-called reversed Fourier optics, the particles enter behind the collecting lens andthus in a converging beam. The advantage of the conventional setup is that a reasonable path length for the sample is allowed within the working distance of the lens. The second setup allows only small path lengths but enables measurement of scattered light atlarger angles, which is useful when submicron particles are present.

• Sprays, aerosols, and gas bubbles in a liquid should be measured directly, provided that their concentration is adequate, because sampling or dilution generally alters the particle-size distribution.In other cases (such as emulsions, pastes, and powders), representative samples may be dispersed in suitable liquids. Dispersingaids (wetting agents, stabilizers) and/or mechanical forces (e.g., agitation, sonication) are often applied for deagglomeration or deaggregation of clusters and stabilization of the dispersion.

• If the maximum particle size of the sample exceeds the measuring range of the instrument, the material that is too coarse can be removed by sieving, and the mass and percentage of removed material are reported.

References:

• USP NF {786}
• USP NF {429}
• ICH Q6A