This document discusses the importance of particulate characterization for pharmaceutical applications. It explains that particle size distribution can significantly impact drug dissolution rates, bioavailability, and stability. Precise control of particle size is critical during crystallization and downstream manufacturing processes. The document also notes that particle shape and morphology are important to understand, as measurement techniques actually measure indirect parameters rather than direct geometry, and particles are rarely spherical. Different characterization techniques may be needed to differentiate between similar samples. The Exova laboratory is equipped to perform a variety of particulate characterization techniques to aid in pharmaceutical development and quality control.

1. Particulate Characterization for Pharmaceutical Applications
by Yuriy Ososkov, Ph.D., P.Eng.
Senior Materials Scientist – Physical Characterization, Exova
Canada Inc., Materials Sciences 2395 Speakman Drive,
Mississauga, Ontario, L5K 1B3, Canada
The concepts of particle engineering and dosage form design have become dominant
themes in pharmaceutical manufacturing. This trend is not simply a reflection of the
development of new, more sophisticated manufacturing methods of particles or
dispersed systems but also recognition of the importance of quality control even in
more traditional manufacturing processes. For drug substances intended for use in
solid or suspension drug product, PSD can have a significant effect on dissolution
rates, bioavailability, and/or stability.
Crystallization is the main separation and purification step for the manufacturing of drug
substances. The PSD obtained during crystallization is influenced by a combination of
various mechanisms that occur during crystallization, such as nucleation, growth,
aggregation, attrition, breakage, etc. Control of PSD during crystallization is critical to
achieving the desired product properties. When the particle size cannot be consistently
controlled during crystallization to meet the desired specifications, an extra processing
step such as dry milling is required. The PSD obtained during the crystallization step

2. affects the efficiency of downstream operations such as filtration, drying, formulating,
and product effectiveness such as bioavailability and shelf life. Thus, the control of
PSD is an important objective during the operation of crystallization process.
At the manufacturing stage, PSD has a critical effect on the content uniformity of solid
dosage forms, where poor content uniformity would result if a drug powder were not
dispersed evenly throughout a mixture with excipients. A leading cause of poor content
uniformity is a mismatch of drug and excipient particle size and density leading to
segregation during sampling and manufacture, especially for low drug to excipient ratio
blends.
However, the diversity of particle treatments, methods of particle size distribution (PSD)
analysis, expression and interpretation of data, and process applications results in
complicated and sometimes confusing criteria for selection, adoption, or relevance of
the available techniques.
Essentially all automated determinations of particle size are obtained indirectly from
direct measurements of some parameter other than the complete geometry. These
parameters are associated with a physical phenomenon in which the particle is
involved. The parameter being directly measured is related to particle geometry by
some law, theory or model describing the physical phenomenon. If the particles under
test are of irregular shape, then the most probable outcome is that the results will
differ. Two particles that, for example, settle with the same velocity (therefore, are the

3. same Stokes size) can scatter light differently (therefore, have different Mie sizes).
Two particles that pass through the same screen mesh have the same sieve size, but
may have very different volumetric size as determined by electrozone sensing.
The apparent simplicity of particle size analysis is deceptive. Particle sizing is a poorly
posed problem. As a matter of fact, only objects of simple geometry, namely spheres,
can be unambiguously described by a single numerical descriptor. The size of
irregularly shaped particles is typically expressed in terms of equivalent spherical
diameters. However, different particle-sizing instruments use various algorithms based
on surface area, volume, or linear dimension to calculate equivalent spherical
diameters. The difficulties encountered when relating empirical information derived
using different methods would not exist if the component particles were spherical. In
the real world of pharmaceutics, particles are rarely (if ever) spherical, and
consequently it is important to understand the importance of particle shape and
morphology.
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. For
instance, the PSD for two materials could be the same, but they could be clearly not
identical under the microscope. It is likely that these two materials would behave

4. differently during processing, or in their final product form. For example, their flow and
abrasion characteristics would be dramatically different. Therefore, particle size data
alone would not allow differentiation between them. As the result, the measurement
and expression of particle size is intimately bound with the shape and morphology of
the constituent units that make up the ensemble of particles.
Physical Characterization group at Exova Canada in Mississauga is equipped with
variety of instrumentation for complete characterization of particulate for
pharmaceutical applications, such as laser diffraction, liquid particulate counter,
specific surface area (BET), helium pycnometry, optical and electron scanning
microscopy combined with digital image analysis software.
Our technical team has wide experience in development and validation of fine particle
methodologies, and this experience and knowledge gives Exova customers a head
start when considering analytical approaches to new applications.
To inquire about our capabilities please contact . . .