Challenges Of Particle Characterisation

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Pharmaceutical Technology Europe

Pharmaceutical Technology Europe, Pharmaceutical Technology Europe-04-01-2011, Volume 23, Issue 4

Particle characteristics can affect pharmaceutical formulations and products in a number of ways, and a variety of techniques are available that enable particle monitoring and characterisation.

Particle size is a potentially important variable in pharmaceutical production and efficacy. In solid or suspension delivery systems, for example, dissolution and solubility characteristics, which impact the bioavailability of the API, are often controlled by particle size, though not necessarily in ways that are intuitively obvious. The Noyes-Whitney equation describes dissolution rate as being directly proportional to particle surface area, so one might expect small particles to dissolve more rapidly than large particles; however, actual dissolution studies show that this is not always the case. In the majority of these instances, this phenomenon can largely be explained by the relative surface roughness of the particles, which gives them a larger surface area.

In suspensions, Stokes' law relates settling velocity (i.e., precipitation or aggregation) to the physical characteristics of the fluid and the size of particles in the suspension. In practice, finer particles create a more stable suspension; however, the stability of particle dispersion also depends on the balance of repulsive and attractive forces. If the particles have little or no repulsive force, there will eventually be some manifestation of instability, such as aggregation. As such, it is not only particle size that matters, but also particle shape, size distribution and zeta potential.

Victor Habbick Visions/Getty Images

Particle size can also affect the behaviour of a formulation during processing. In direct compression tabletting, particle size can influence segregation behaviour and the compressibility of a formulation that, in turn, can affect the consistency of tablet weight and composition, how the press operates, and the mechanical properties of the finished product.

Particle size also has a critical effect on the content uniformity of solid dosage forms, with poor results often arising from a mismatch of drug and excipient particle size and density. Poor content uniformity may also result if drug particle size distribution is too large, but it is generally desirable to approach the upper edge of the permitted drug particle size range because reducing particle size too dramatically can exacerbate drug agglomeration and mixing problems.1

Similarly, particle size can affect the flow properties of powders and pastes. Increasing the polydispersity of particle size in powders can improve flow properties; for example, in the case of powders subject to flow in an industrial process, a bimodal distribution of particle sizes can also ensure better flow during processing.1 For pastes, where viscosity is often important, there is usually an optimum particle size distribution (PSD) that yields minimum viscosity whilst maintaining the particle volume fraction. The PSD will also have a direct influence on the texture of the finished product.

Overcoming the challenges

There are several methods, some of which are outlined below, that can be used to investigate particle characteristics. All give useful information on their own, but it is often more instructive, or simply necessary, to use the techniques to complement each other. Using laser diffraction methods to understand particle size distribution, and microscopy to understand shape, for example, helps to build a more detailed picture of why a powder behaves in a certain way.

It is also important to note that different techniques for measuring particle size can yield different answers. This is not a new observation. In 2004, the AAPS Journal published a report on particle size analysis and called for greater harmonisation of methods and a wider appreciation of the difficulty of reconciling results obtained by different methods of particle sizing.2 Since then, observers have noted that some progress has been made via the Laser Diffraction Measurement of Particle Size USP monograph (USP <429>),3,4 released in 2005, and the USP written standards regarding lipid emulsions (USP <729>). The European Pharmacopoeia also has a chapter on laser diffraction5 and, more recently, ISO13320:2009 was published, creating a new standard, and guiding the way for robust method development.


Linking laboratory with production

One key factor influencing the choice of technologies for particle size analysis is the desire to correlate lab results with production information gathered at various stages of the product cycle. However, each stage of product development and manufacture has a different focus, meaning that the analytical tools employed will vary.

Quality by Design (QbD) encourages the development team to identify and quantify correlations between key product variables and clinical performance, and to understand how these are controlled by the manufacturing process from the outset. At this stage, there is an urgent need for detailed knowledge and for instruments that provide a cost-effective route to its acquisition.

As a project moves through pilot plant development and into manufacture, the focus switches to tracking process dynamics and continuous monitoring, which means the measurement speed of the particle characterisation technology employed becomes critical. In particular, there is a need for systems that enable real-time process scoping, optimisation, monitoring and control. During production, effective analysis allows manufacturers to ensure that product quality targets are met consistently, thereby reducing reliance on pre-release quality control testing.

When it comes to quality control, the demands on particle characterisation systems change again. Here, one may not need to know the actual size of the particles. It may be enough to have a parameter that can be measured reproducibly and that correlates with a known performance characteristic of the drug. For example, if the particles are non-spherical, a Laser Light Scattering method may give a wildly inaccurate value for the true diameter of the crystals, yet give results that are consistent and, therefore, allow the setting of a specification.

Beneficial techniques

Because the tools employed will vary at each stage, maintaining a consistent specification during transitions from one technique to another can be complicated. As such, technologies that can be configured for both laboratory and process use, or those that neatly dovetail, are advantageous. Laser diffraction and automated image analysis are two such techniques.

Laser diffraction

Laser diffraction is a rapid measurement technique and an established on-line technology that enables real-time, on- or in-line particle size analysis for both wet and dry systems. Off-line laser diffraction can also be highly automated and robust after successful method development.

Laser diffraction can be used to develop particle size specifications in the early stages of a project, and then transferred into production via on-line technology. Many powders have particle size specifications and laser diffraction is often used as the sizing technique of choice for quality control in this regard. For some applications, however, size data alone will be insufficient to either fully characterise or define a material.

Imaging technology

As imaging technology has become more freely available, the influence of particle shape on performance has become increasingly well appreciated. Automated imaging overlays size data with statistically relevant information about shape, and can be useful for detailed development work in troubleshooting and root cause analysis. If two samples behave differently but are classified as identical by particle size analysis, morphology of the particles may hold the key.

Imaging is much faster than manual microscopy — data for tens of thousands of particles can be obtained in minutes — and, importantly, it produces more statistically relevant data. Parameters such as circularity, convexity and elongation can be measured and used to precisely define the shape distributions of a particle population. Each image can be scrutinised by eye if necessary, whereas size versus shape plots enable the identification of discreet particle populations like APIs and excipients with overlapping size distribution. The integration of spectroscopy into imaging systems adds a further powerful dimension to automated image analysis; Raman spectroscopy, for example, can characterise particles by size, shape and chemical composition.

Combining the benefits

Switching between image analysis and laser diffraction needs care — image analysis software is constrained to two dimensions — but it is entirely feasible and offers many advantages; for example, during method development for laser diffraction, imaging can identify the presence of any agglomerates. Imaging also adds a layer of detail that cannot be obtained through laser diffraction particle size analysis alone.

There are also times when manual microscopy proves a valuable addition to the particle characterisation armoury. In particular, microscopy plays a valuable role in identifying unknown and unwanted particles, i.e., foreign bodies, when linking X-ray diffraction to the scanning electron microscope to obtain data on chemical composition. In addition, it can be useful for assessing the mixing quality of two ingredients within a tablet. Similarly, infrared imaging microscopy can be used to analyse the distribution of organic molecules or particles in complex mixtures, such as tablet formulations and sediments. In both cases, these techniques can demonstrate whether there is good content uniformity and, by implication, whether there is good distribution of API across a production run.

Particles in practice

It is one thing to know the size, shape and appearance of particles, but one also needs to know how these parameters affect product and process performance. As noted above, small particles don't necessarily dissolve more rapidly than large particles of the same chemical.

In early phase development, it is critical to investigate how particles of the proposed new API will dissolve in the body. Using methods specified in the pharmacopoeia, one can mimic the environment of the mouth and gut, and determine where in the GI tract an API is likely to dissolve. This information can potentially justify whether the candidate molecule is worth pursuing. One might also investigate whether the particle size within the finished product has an impact on release rates.

Rheological studies are also valuable because subtle changes to particle size, distribution and shape can affect the rheology positively or negatively. With medicines that are suspensions, for example, it is important to control viscosity to prevent settling during storage, and to mitigate inconsistent dosing.


Many techniques are available to establish, measure and monitor particle characteristics, and there is much that can be learned about the effect of particle size and morphology on end product performance. However, when using results to set specifications or manage quality control, it is always necessary to seek out the detail of the methodology used to generate data because different methods 'see' particles in different ways.

To take an obvious example, one might have a particle size specification such as "50% of particles (by mass) must be less than 80 μm" set after sieve tests on representative batches. This would not necessarily be confirmed by analysis of the same batches using laser diffraction and reporting the d50 (diameter of the 50th percentile), even though, at first sight, the two specifications might seem to be equivalent. In the case of laser diffraction, the key parameter is particle volume rather than mass, and particle orientation and shape are not accounted for in the same manner.

Using techniques that permit the recording of visual images makes it possible to give further supporting evidence to the robustness of a particle characterisation method that generates only numeric data. In this way, it is possible to ensure that the procedure is characterising primary particles and not agglomerates, and that the method of analysis does not have a destructive effect on the distribution being recorded.


The author would like to acknowledge Malvern Instruments.

Victoria Jones Laboratory Manager, Physical Science Laboratory, RSSL


1. P. Kippax, Pharm. Technol. Eur., 21(4) (2009).

2. D.J. Burgess et al., AAPS J., 6(3), 23–24 (2004).

3. J. Netterwald, Pharmaceutical Formulation and Quality (December/January 2010).

4. US Pharmacopoeia

5. European Pharmacopoeia, Chapter 2.9.31, Laser Diffraction Measurement of Particle Size, Supplement 5.6 (2006).