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