W. Richard Bowen and Nidal Hilal 4

174 6. NANOSCALE ANALySIS Of PHARMACEUTICALS by SCANNINg PRObE MICROSCOPy
aimed at providing storage of the active therapeutic ‘stealth’ functionality
to avoid the body defences as well as a targeting element. The additional
trend towards the delivery of protein- and DNA-based medicines
through new alternative delivery routes such as inhalation has also
increased this need for nanoscale analysis. Such complex systems require
analysis capable of minimal disruption due to sample preparation and
the ability to operate in a ‘physiological’ environment. This demand
often exceeds the capacity of traditional analytical approaches to provide
an effective understanding of this new generation of therapeutics.
This chapter will highlight the role of atomic force microscopy (AFM)
and other scanning probe microscopies (SPM) in the qualitative and
quantitative analysis of pharmaceuticals, highlighting both imaging and
force data acquisition modes. These microscopes have enabled the study
of pharmaceutical devices [1–3] and drug particles [4–6] with minimal
pre-treatment in both air and liquid at the nanoscale level. The potential
for SPMs, and AFM in particular, is now being exploited as an integral
part of formulation, in both academic and industrial research. It is of
course important to note that whilst SPM-based solutions do represent an
increasingly important part of the analysis of pharmaceuticals, they are
best applied with complementary approaches, such as Raman spectroscopy
or diffraction-based techniques, which can provide chemically specific
and 3D structural data.
6.2 The AFM AS A ForCe MeASureMeNT Tool IN
PhArMACeuTICAlS
Most pharmaceuticals are produced as solid dosage forms (e.g. tablets,
capsules, inhalable powders) and hence their manufacture inevitably
involves the handling and manipulation of powdered materials. These
powders can have particles ranging from submicron to many hundreds
of microns in size. An understanding of how the mechanical properties
of these particles and the forces between them influence factors such as
processability and stability is an important feature of formulation development.
Indeed, in some cases, the final form of the drug (and other
materials in the medicine (the excipients)) is loose powder, as e.g. in a dry
powder inhaler (DPI). Here then, the successful delivery of the drug itself
relies on an intimate understanding of particle properties and their interactions.
Until recently, the direct assessment of particle-particle and particle-device
interactions relied upon long-established bulk methods that
deal with large numbers of particles, such as the centrifugal technique
[7, 8]. Whilst effects such as cohesion and adhesion phenomena can be
studied, these data reveal little concerning the nature and interplay of the