Discovery and Formulation - Emerging Raman Applications and Techniques in Biomedical and Pharmaceutical Fields - page 214

more than one crystalline form and the pharmaceutical development process
requires that each form including the amorphous form is characterised using
a variety of techniques [16]. Properties such as bioavailability, solubility and
stability of the API in drug product are often directly related to the phys-
iochemical properties of the polymorph(s) present [17]. In addition, different
polymorphs often adopt different morphologies. These may display vastly dif-
ferent physical properties, including flowability and compaction, which may
in turn influence the manufacturability of the drug product [18]. All of these
factors have implications for the safety, ecacy and manufacturability of the
drug product. Regulatory bodies therefore require polymorphic form to be
closely monitored and controlled unless proof of form bio-equivalence can be
demonstrated.
In recent years there has been increasingly more interest in determining
the amorphous content of pharmaceutical materials. This is due to

a) regulatory requirements;
b) amorphous materials having a higher solubility (but lower stability) than
crystalline forms. This may be particularly important for formulation
delivery of API salts with low aqueous solubility;
c) crystalline disorder caused by processing (e.g. milling, micronisation).
These amorphous surfaces can provide the sites for the formation of unde-
sirable API polymorphic forms and are of great interest in inhaled prod-
ucts where the API particle size is in the order of 2-10 μ m.

Raman spectroscopy has been used to assess the relative composition of
crystalline and amorphous in bulk samples. The vibrational spectra of amor-
phous materials typically have fewer and broader bands than crystalline ma-
terials due to the molecular disorder. By building reference training sets with
different crystalline to amorphous ratios, chemometric methods can be devel-
oped to determine the amorphous content of provided samples. However this
does not truly reflect the types of samples of most interest. These chemomet-
ric models are based on mixtures that are comprised of either crystalline or
amorphous particles. Of far more interest and significantly more challenging is
the determination of amorphous material on particle surfaces and interfaces.
Studies by Ward et al. [19] have started to address this issue using atomic
force microscopy (AFM) and confocal Raman microscopy. Using d-sorbitol, a
pharmaceutical excipient with four polymorphic forms and a relatively stable
and easy to produce amorphous form, these techniques have been used to
study different solid state phases on sample surfaces. After preparing discs of
crystalline d-sorbitol a microthermal analyser was used to produce localised
areas of amorphous material. Figure 9.1 shows the Raman spectra of the
initial crystalline and subsequent amorphous d-sorbitol. The two forms can
be distinguished from their Raman spectra, and band broadening is evident
in the amorphous form. As the d-sorbitol changes from a crystalline to the
amorphous phase the peak width at half height for the 878 cm − 1 band