Discovery and Formulation - Emerging Raman Applications and Techniques in Biomedical and Pharmaceutical Fields - page 215

Fig. 9.1. Raman spectra of ( left ) crystalline d-sorbitol and ( right ) quench cooled
glassy (amorphous) d-sorbitol. Reproduced from [19]
(attributed to the C-C-O stretch) changes from 15 to 34 cm − 1 . This allowed
the depth and distribution of the amorphous d-sorbitol through the crys-
talline bulk to be determined. This approach shows promise in providing a
better understanding of batch-to-batch variations in crystallinity that lead
to formulation and/or manufacturing problems which cannot be detected by
bulk Raman methods.
Polymorph and amorphous form identification must be made in the solid
state as all structural information is lost when employing wet chemistry meth-
ods. The solid state techniques most commonly employed by the pharma-
ceutical industry for polymorph characterisation are powder X-ray diffrac-
tion (PXRD), differential scanning calorimetry (DSC) and solid state NMR
[18]. However, owing to its versatility, speed of analysis and minimal require-
ments for sample preparation, Raman spectroscopy is becoming a more com-
monly used tool for analysis and characterisation of pharmaceutical solids [20].
Of all the vibrational spectroscopies, Raman has the widest spectral range
(4000-30 cm − 1 ). The lower frequency range covers those frequencies associ-
ated with crystal lattice vibrations and these can be particularly informative
in discriminating between different crystalline and amorphous forms of a ma-
terial [21]. However, subtle changes in the unit cell, for example in the position
of an alkyl chain, are rarely discriminatory when using vibrational spectro-
scopic methods, so other methods are preferred in the identification of new
forms. This is because FT-IR and Raman spectroscopy are both short-range
probes obtaining information from chemical functional groups and structural
fragments within a molecule, whereas X-ray diffraction methods are much
longer range techniques which gather information on the whole molecule unit
cell. Due to these considerations DSC and PXRD are the “gold standard”
analytical methods for polymorph identification due to their better sensitiv-
ity to changes in the unit cell. Raman spectroscopy provides an important
supportive role in the characterisation of API forms with spectra and peak
tables being used as part of the patent applications for new materials.