PharmTech: What challenges exist with regard to understanding bulk-powder attributes?
Freeman (Freeman Technology):
I think it is reasonable to say that the pharmaceutical industry's ability to understand how bulk powder properties impact
process behavior has been constrained by a lack of reliable bulk powder property data. The reproducible measurement of defining
powder characteristics, such as flowability, has long been a goal, but the results have been mixed. Traditional techniques,
such as flow through an orifice and tapped density methods, are not ideal for the extended, detailed experimental work required
to support QbD. Shear-cell measurements are ideal for understanding flow in hoppers, but are less useful for understanding
lower stress processes, such as mixing, filling and aerosolization. Here, different measurement techniques are required.
Powder testing has developed considerably in the past decade, including the introduction of dynamic testing. Dynamic characterization
reproducibly and directly measures powder flowability, for conditioned powders and for those that are consolidated or aerated,
thereby generating reliable and valuable information for process development. Used in combination with bulk and shear property
measurement, dynamic testing enables the kind of multifaceted powder characterization required to fully rationalise in-process
With these techniques in place, it is now possible to develop a detailed understanding of the way bulk properties influence
tableting, granulation and many other frequently employed unit operations. This type of knowledge development remains a work
in progress, but the goalposts shift too. Faster tableting speeds are one example, but the long-term objectives of continuous
production in integrated manufacturing suites adds another layer of complexity, requiring testing strategies that provide
the deepest and most comprehensive information.
Levoguer (Malvern Instruments):
Generally speaking, my area of expertise is the measurement of particle properties rather than bulk powder attributes of the
material, such as flowability and permeability. However, I've recently observed that some of our more experienced laser diffraction
customers within the pharmaceutical sector are now using particle size analyzers to directly access information about the
cohesivity of the sample because this is a useful property for tablet blend optimization.
Sample dispersion is an essential element of laser diffraction particle-size analysis. In dry measurement, dispersion conditions
are established by conducting a pressure titration, which involves gradually increasing the pressure of the dispersing gas
until a steady particle size is measured and/or the results obtained are identical to those generated with wet dispersion.
Agitation and sonication are applied to achieve wet dispersion. In either case, the development process used to develop a
robust method yields parameters that effectively quantify the strength of particle-particle interactions within the powder
In state-of-the-art laser diffraction systems, dispersion conditions can be very precisely controlled and this measure of
cohesive strength can therefore be sufficiently sensitive to give useful information for tablet blend optimization.
PharmTech: What technological gaps exist among the industry for fully understanding the material properties of powders used
in a tableting process?
Freeman (Freeman Technology):
Particles exhibit a wide range of mechanical and chemical properties. Several of these are commonly recognized as being highly
influential with respect to in-process performance and product quality, and are often well defined as part of the specification.
However, other properties, which may be even more important in some instances, such as particle shape, roughness, porosity
and stiffness, to name just a few, are rarely considered in a specification because they are either too difficult to measure
directly or can't be measured at all. Nevertheless, that doesn't exclude them from influencing the overall bulk material properties
and, consequently, the in-process performance of the powder and the final product quality.
Direct measurement of many of these properties will only be achieved with further technological advances, but they will be
required if the goal of "mathematical QbD" (accurately predicting tablet or granule properties from a knowledge of a range
of particle properties) is to be achieved. In the interim, recent advances in bulk powder measurement techniques, simulating
the conditions powders observe in the process environment and quantifying their response to those conditions, are likely to
provide the best opportunity for understanding the relationship between bulk material properties, process parameters and final
Levoguer (Malvernns Itruments):
As I've previously suggested, one of the reasons why our customers measure parameters, such as particle size and shape, is
because they are known to correlate with processability issues such as flowability, compressibility and the likelihood of
blend segregation. These relationships are widely recognized, but my understanding is that they are not yet quantified in
ways that help to establish optimal bulk powder properties. I would, therefore, point to lack of knowledge in the area of
correlating particle and bulk powder properties as a gap that needs to be filled in the future.
As I noted previously, the advancement of automated imaging has made it much easier to access the shape data needed to extend
our understanding in this important area and we have done some work in this area ourselves with Freeman Technology looking
at the effect of particle size and shape on the bulk properties of lactose (1). This is an interesting area of research and
one that I'm sure will receive further attention from the pharmaceutical industry as it works to extend understanding of how
to make powders behave as required.