W. Richard Bowen and Nidal Hilal 4

6.2 THE AfM AS A fORCE MEASUREMENT TOOL IN PHARMACEUTICALS 175
fundamental forces involved (e.g. van der Waals, electrostatic, capillary).
Access to such information is beneficial not only to the assessment of a
formulation, but also to establish the basis of any required particle modification
and optimisation.
Just as particle interactions can be probed using AFM, the nanoscale
mechanical properties of powders can also be investigated. Previously,
this could only be derived from bulk techniques, where powders are
compressed into miniature beams and three-point bending tests are
performed. The need for relatively large amounts of powder and to
account for the porosity of the beams has limited the applicability of this
approach. Even using miniaturised beams, milligram quantities of material
are required, preventing screening of active pharmaceutical ingredients
at early stages of development [9, 10]. Here, we consider how AFM
has been used to address both particle interactions and the measurement
of the mechanical properties from single particles.
6.2.1 Particle Interaction Measurements
The ability to study single-particle interactions and the forces involved
became possible with the advent of the AFM in 1986 [11–13]. In particular,
the use of AFM in the so-called ‘colloidal probe’ technique, whereby
the force of interaction between a spherical bead attached to the AFM
cantilever and a planar surface was studied, revealed the potential of this
approach [14]. Importantly, a single particle (e.g. drug) attached to the
AFM cantilever can be used for a series of comparative experiments challenging
different substrates. In addition, the ability of AFM to work in a
variety of environments, such as controlled humidity and in liquids, is
significant for pharmaceutical applications.
The first example of this approach being used for a pharmaceutical
powder examined the differences in the adhesion of lactose particles to
two gelatin DPI capsule surfaces [15]. It is important when attaching
such individual drug particles to an AFM cantilever that their contacting
region remains free from any adhesives employed or damage during
attachment. An example scanning electron microscope (SEM) image is
shown in Figure 6.1, where a drug particle is attached to an AFM cantilever.
Typically, to prepare such a probe would involve the use of a minute
amount of glue on the end of the cantilever to which a particle is attached
using a micromanipulator or the AFM itself. This relatively labourintensive
sample preparation currently limits the number of different
particles used within one study (usually to no more than five). The accessible
particle size is typically in the range between 0.5 �m and 50 �m. For
very small and/or cohesive particles (1 �m or less), more than one may
become attached to the lever; however, as long as only one comes into
contact with the surface to be challenged, this is acceptable.