![]() If particle shape is important to API or formulation performance, this critical information is lost without a secondary orthogonal analytical method. A needle-like particle having a length of 100μm, for example, may have an equivalent sphere diameter of only 5μm. However, where particles deviate from the ideal spherical habit, laser diffraction data provides no insight into particle shape. For example, a hypothetical data set might show 90% of the measured particles as ≤1.0μm in size using a number based distribution whereas, that same data would be reported as 90% of the measured particles are ≤5.2μm in size using a volume-based distribution.įurthermore, laser diffraction results are nearly always expressed in terms of ‘equivalent sphere’ diameters, thereby allowing a single numerical value to express the size of a particle. In a laser diffraction histogram, identical raw data may be displayed as both a number-based distribution or a volume-based distribution. Conversely, a number-based distribution is influenced primarily by the smallest and most abundant particles in the sample. This is why D(v,0.9) values – the volume-based level below which 90% of particles were measured and which have the greatest influence on dissolution rate – are so sensitive to subtle changes in milling parameters. In a volume-based method the overall size distribution is influenced primarily by the largest particles present. Laser diffraction particle size analysers typically present data as a volume-based distribution, whereas imaging techniques often present data in numerical terms. If left undispersed, these agglomerates would be measured by laser diffraction as >100μm. The scanning electron micrograph (Figure 1) clearly shows discrete particles of less than approximately 2-3μm in size, which form irregular agglomerates exceeding 100μm in diameter. As such, the importance of a secondary orthogonal confirmatory technique, particularly optical or scanning electron microscopy, to qualitatively evaluate particle size distribution provides important context. Laser diffraction instruments cannot distinguish between discrete particles and particle aggregates. Whereas a method intended to assess particle agglomeration may use reduced, or no, sonication to preserve sample agglomerates. A dry dispersion method may employ high disperser pressures to ensure separation of discrete particles. A wet dispersion method for discrete particle size measurement typically employs ultrasonication to physically disrupt cohesive particles, and the use of surfactants in the dispersion medium to ensure no re-agglomeration occurs prior to measurement. When developing a size-based method for micronised or milled API, the analyst must determine what they want to measure, eg, the size of discrete or agglomerated particles, or both. Laser measurement techniques and methodology considerations Sub-samples for analytical testing can then be generated using mixing and dividing techniques such as spin riffling, cone and quartering, or simple rotation/inversion of the lab sample before taking an aliquot for analysis. When sampling powders from large bulk containers it is good practice to obtain a sample representing the full height of the powder bed from top to bottom, using a core sampling thief, for example. Sampling bias may be further compounded with subsequent sub-sampling in the laboratory or elsewhere. ![]() Although this concept is widely understood, it is often overlooked. This applies to analytical sub-samples as well as bulk samples. Over time, smaller particles in a sample will migrate to the bottom while larger particles will become more concentrated at the top of the container. All powders will segregate during shipping, handling, and even warehouse storage. Generating meaningful particle size data starts with representative sampling. Extremely precise and repeatable measurements are attainable, but understanding the limitations of this technique is critical to acquiring meaningful information. Therefore, representative sampling, sample homogeneity and particle morphology are important because of the small sample sizes, potential settling of the sample, etc.Ī wide range of techniques are available to determine particle size however, the most broadly used technique is laser diffraction. Particle size analysis has become a proxy for routine surface area measurement. PARTICLE size is an important attribute in APIs, solid oral drug products (tablets and capsules – impacting on homogeneity, flow and processing), and as a critical quality attribute in semi-solids (suspensions) and sterile liquid products (injectables). ![]()
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