Particle shape - an important parameter in

pharmaceutical manufacturing
Dr Deborah Huck, Application Specialist Vision Systems
Malvern Instruments Ltd, Enigma Business Park, Grovewood Road, Malvern,
Worcestershire, UK, WR14 1XZ

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The advent of rapid and reliable measurement technologies, together with the FDA’s PAT
(Process Analytical Technologies) initiative, has increased the use of particle shape analysis
within the pharmaceutical industry. Particle shape, like particle size which is routinely
measured and controlled, can directly influence product performance and its measurement
can lead to improved process and product understanding. Here we consider the importance of
particle shape measurement for the pharmaceutical industry, with reference to the aims of the
PAT initiative, and highlight the modern image analysis techniques available for sensitive
size and shape characterization.

Why measure particle shape?

Often, manufacturers producing a particulate product need to identify and understand the
differences between batches, either for product development reasons or for quality control
purposes. For some applications particle size analysis generates enough data for sample
differences to be fully rationalized, but for applications where samples are very close in size,
measurement of subtle variations in shape may be necessary.

Figure 1 shows two different samples. The particle size distributions for each material could
be the same, but they are clearly not identical. It is likely that these two materials would
behave differently during processing, or in their final product form. For example, their flow
and abrasion characteristics would be dramatically different. Particle size data alone would
not allow differentiation between them.

Fig. 1: Two different samples could be reported as identical

using a size-only distribution.

PAT

The FDA’s PAT initiative, an effort to improve cGMP by providing a regulatory framework
for the introduction of new manufacturing technologies for the pharmaceutical industry, is
ultimately designed to improve process control in the sector. Improved process control
delivers greater efficiency, less waste and lower production costs. It will therefore allow the
industry to respond more effectively to environmental and economic challenges.

Currently, many manufacturing operations are based on time-defined endpoints; for example
‘blend for 10 minutes’ or ‘mill for 1 hour’. The spirit of the PAT initiative is to move away
from this approach, to one where endpoint is defined in relation to a property that is closely
linked to product quality - granule size, morphic form or blend uniformity for example.
Material with the desired properties is then produced more consistently and waste is
minimized. This approach requires identification of an appropriate variable, with effective
monitoring and control of the selected parameter.

Particle characterization using image analysis

Particle shape and size data can be generated using automated image analysis techniques,
complementing both microscopy and laser diffraction for particle characterization. In contrast
to manual microscopy, image analysis generates statistically relevant data with no subjective
bias, allowing shape, and its effects, to be studied systematically. Image analysis generates
number-based distributions and is therefore extremely sensitive to the presence of fines or
small numbers of foreign particles. In addition, individual particle images are recorded,
allowing visual detection and verification of agglomerates or contaminants.

Image analysis procedures involve the capture of images using transmitted or reflected light,
a lens system and a CCD. Movement between the sample and the magnification lens allows
scanning of a large number of particles for the production of statistically relevant data;
typically several thousand particles are measured per minute. Multiple shape parameters are
calculated for each individual particle and collated into distributions with all the associated
distribution parameters.

Particle orientation

Particle orientation is critically important for effective characterization of particle shape by

image analysis. Figure 2, which shows an analysis of a sample of monodisperse needle-
shaped particles, clearly illustrates the problem associated with random orientation. The
shape and particle size data produced shows a polydisperse sample. The bank of images
illustrates why. The camera and software are seeing a selection of different 2D views of
similar particles – the random orientation is hiding the genuine primary morphology of the
sample.

full-screen

full-screen

Fig. 2: Shape analysis of monodisperse needle shaped

particles.
Consistent orientation is critical for the identification of real morphological differences.
Particles may be presented showing their largest surface area, their smallest surface area or
something in between. Which area is analyzed is less important than the consistency of
presentation. However, as the largest area orientation is more closely correlated with surface
area and volume-based data - and easier to achieve - this approach tends to be adopted.

Defining particle shape

Various different aspects of particle shape are of interest and a range of descriptors has been
devised to allow particle shape to be quantifiably described. No single shape descriptor is
suitable for all applications. The following three parameters, which are all normalised
(defined to have values lying in the range 0 – 1) are frequently used to quantify different
aspects of particle shape.

Elongation

Elongation provides an indication of the length/width ratio of the particle and is defined as
(1-[width/length]). Shapes symmetrical in all axes, such as circles or squares, will tend to
have an elongation close to 0 whereas needle-shaped particles will have values closer to 1.
Elongation is more an indication of overall form than surface roughness (see figure 3) - a
smooth ellipse has a similar elongation to a ‘spiky’ ellipse of similar aspect ratio.

Fig. 3: Elongation.

Convexity

Convexity is a measurement of the surface roughness of a particle and is calculated by

dividing the particle area by a ‘total area’, best visualized as the area enclosed by an
imaginary elastic band placed around the particle. A smooth shape, regardless of form, has a
convexity of 1 while a very ‘spiky’ or irregular object has a convexity closer to 0 (see figure
4).

Fig. 4 : Convexity.
Circularity

Circularity is a measurement of the ratio of the actual perimeter of a particle to the perimeter
of a circle of the same area. A perfect circle has a circularity of 1 while a very ‘spiky’ or
irregular object has a circularity closer to 0. Intuitively, circularity is a measure of irregularity
or the difference from a perfect circle. Figure 5 shows how circularity is sensitive to both
overall form (like elongation) and surface roughness (like convexity). This shape factor is
particularly useful for applications where perfectly spherical particles are the desired end
product.

Fig. 5 : Circularity.

A further parameter frequently used in particle characterization is:

Circle equivalent diameter

Circle equivalent diameter is calculated by measuring the area of a 2D image of a particle and
back-calculating the diameter of a circle with the same area. It is one of many equivalent
values used to define particle size and is calculated easily from image analysis data. Circle
equivalent diameter calculation depends upon which 2D view is captured and hence may not
be directly comparable with alternative particle size measuring techniques, particularly if the
particles are not spherical.

Practical example of sensitivity to shape

The following exemplifies the sensitivity of one pharmaceutical process to particle shape.
One of four batches of a pharmaceutical excipient was continuously failing at the tabletting
stage of a manufacturing process. This was proving to be highly expensive since the
tabletting process was at the very end of the manufacturing process where all the value has
been locked into the product.

The tablet producer wanted some way of identifying the failed batch much earlier – ideally as
a raw material. Traditional microscopy or ensemble sizing methods could not distinguish
between the four batches being used.

Automated image analysis was used to evaluate the average convexity of each of the four
batches. Convexity is a measure of surface roughness or ‘spikeyness’ of the particle surface
and the failed batch was found to consistently exhibit a lower average convexity than the
other three good batches (Figure 6).
 Fig. 6.

In conclusion

The need for higher quality, higher sensitivity analytical techniques to increase process
understanding within the pharmaceutical industry has been highlighted through the PAT
initiative. Image analysis, an increasingly accessible option thanks to advances in PC
processing power and digital camera technology, is particularly suited to analyzing size and
shape and is a valuable tool for the sector. With particle shape and size data readily available
it becomes possible to more effectively define process end-point and rationalize differences
in the behaviour of different batches. In this way image analysis technology is delivering
significant improvements in both process efficiency and product quality.