Discovery and Formulation - Emerging Raman Applications and Techniques in Biomedical and Pharmaceutical Fields - page 218

processes such as milling/micronisation, wet granulation (particularly hydrate
formation) and tabletting (form conversion via pressure changes). Similarly
the most stable polymorphic form at room temperature may not be the most
stable form at a different temperature. For these enantiotropic systems it is
important to know under what conditions and how conversion takes place
(e.g. kinetically or thermodynamically) as this may impact on how the for-
mulated API is manufactured or stored. The relationships between forms and
their thermodynamic stability can be represented in flowcharts and phase
diagrams as illustrated in Fig. 9.2 for the monotropic solid state forms of
prilocaine hydrochloride [36].
Fig. 9.2. Flowchart of prilocaine hydrochloride solid state forms and melt with
transformation temperatures under ambient pressure conditions ( left ) and semi-
schematic energy/temperature diagram of the polymorphs ( right ). Key: H , enthalpy;
G , Gibbs free energy; Δ H f , heat of fusion; Liq, liquid phase (melt). Reproduced
from [36]
In the construction of these diagrams the use of Raman is limited and
generally restricted to form identification. However, it is when Raman spec-
troscopy is coupled to other techniques that the information required to under-
stand API forms and their behaviour is more fully realised. The combination of
thermal analysis instrumentation with Raman systems has been particularly
beneficial, and there has been a clear progression of purpose-built instrumen-
tation to observe the relationship of material forms at non-ambient conditions.
Szelagiewicz et al. [37] used a standard light microscope hot stage to observe
and heat individual particles of paracetamol and record their Raman spec-
tra at elevated temperatures. Using very little material (e.g. micrograms) this
approach allowed new API forms to be produced at non-ambient conditions