W. Richard Bowen and Nidal Hilal 4

186 6. NANOSCALE ANALySIS Of PHARMACEUTICALS by SCANNINg PRObE MICROSCOPy
calorimetry. However, such approaches cannot reveal the spatial distribution
of these components. An adaptation of AFM that can achieve this is
the Scanning Thermal Microscope (SThM) [50]. Here, the normal silicon
cantilever is replaced with a Wollaston wire probe, brought to a sharp
apex in the form of a cantilever. The spatial (and thermal mapping) resolution
of such probes is on the order of a micron. Whilst this is useful,
they also have the additional ability to apply heat locally to a surface and
to record the power required to deliver a constant temperature increase to
that point in the sample (in a manner analogous to Differential Scanning
Calorimetry (DSC)), therefore providing detailed thermal characterisation
at that point on a sample (the so-called Local Thermal Analysis (LTA)).
To date, LTA has been the main area of application of this approach in
pharmaceuticals.
Six et al. have demonstrated the ability of SThM analysis to distinguish
and identify phase-separated material in solid dispersions of
itraconazole and Eudragit ® E100 polymer [51]. Such dispersions of
a poorly soluble drug in a soluble matrix represent a classic route to
improving the bioavailability of such drugs. SThM images of dispersions
containing 10%, 40% and 60% itraconazole showed an increase in
surface roughness with an increase in drug loading, possibly linking the
rough surface areas to phase-separated drug. Phase-separated regions of
the drug are not desired as they would be less liable to release the active
ingredient than molecular dispersed drug. LTA has been used to characterise
the different phases by a comparison of the glass transition (T g) of
different dispersions with that of the pure compounds of drug and polymer.
LTA showed that the penetration of the probe tip into a sample of
pure itraconazole occurred at around 333 K, which is in good agreement
with the previously determined T g for the drug by DSC of 332.4 K. In contrast,
the penetration of the probe tip into pure Eudragit ® E100 occurred
at a much higher temperature of 383 K compared to its T g of 318 K determined
by DSC and was linked to the fragility of the sample [51]. It was
also observed in dispersions with low drug loading (10%) that the probetip
penetration was at a temperature in between the T gs for itraconazole
and Eudragit ® E100, an indication of intimate mixing of the components.
At high drug loading (60%) dispersions, the T g was similar to that for the
drug, indicating separation of the components.
In another study by Sanders et al. [52], SThM combined with LTA
was used to distinguish between two polymorphs of cimetidine, types
A and B. These two pharmaceutically useful anhydrous polymorphs of
cimetidine had previously been tentatively distinguished by AFM phase
imaging in a variable humidity environment [48]. An understanding
and ability to detect and distinguish between different polymorphs in
drug formulations is of particular significance, as different polymorphs
can have different physicochemical properties and can convert from one