RAMAN SUPPLEMENT


even well below the glass transition temperature (Tg


= 43°C)12,13 , depending on how


the amorphous state is prepared. Identification of the different crystalline forms of a molecular system can be performed in the low-frequency range (Figure 4a), distinctive of the symmetry of the long-range order. IMC has a rich polymorphism composed of three crystalline forms, and is characterised by an original α-γ monotropic system, whose more stable (γ) form does not have the most compact molecular packing14


. The Raman susceptibility of the


FIGURE 4Raman spectra of crystalline and amorphous (AS) states of indomethacin a) in the low-frequency range, b) in the C = O stretching region


different from the glass, corresponding to a polyamorphism situation. Only Raman spectroscopy makes it possible to identify this apparently amorphous state as corresponding to nanocrystals embedded in the matrix of non- transformed liquid9,10


, as shown in Figure 3 on


page 12. Consequently, RS is a very sensitive structural probe and has important applications both in the field of fundamental physics, to analyse polyamorphic situations or devitrifica - tion process, and in the pharmaceutical industry as shown in this paper.


“Tabletting involves the direct compression of the API in the


40 – 400 MPa pressure range”


Analysis of the amorphisation and crystallisation mechanisms in indomethacin (IMC) IMC is typically a poor water-soluble drug11


amorphous solid state (Figure 4a) is considered the representative of the VDOS, and the intensity of χ”(ν) corresponds to the intensity of the lattice modes of the different crystalline states, considering no overlapping between inter and intramolecular modes. Additional intensity is clearly observed below 25 cm-1


in the


amorphous state, which has no correspondence in the spectra of the crystalline phases. It is usually interpreted as corresponding to an excess of VDOS reflecting the deviation of g(ν) from the ν2-behaviour in the low-frequency range. As a consequence, the plot of χ”(ν)/ν2 (inset ofFigure 4a) exhibits a very low-frequency peak, the so-called boson peak15,16


. The glassy , and


its bioavailability is enhanced in the amorphous state. However, it is well known that IMC exhibits different crystallisation processes


state and the different crystalline phases of IMC can be identified by Raman or IR spectroscopies in the C = O stretching region17,18 1750 cm-1


1550 cm-1 intense band located at 1697 cm-1 ,


plotted in Figure 4b. The sharp and in the


FIGURE 5 Raman spectra measured at different cryogrinding times from the stable γ-form: a) χ”(ν) spectra in the low-frequency range; the inset shows the enhancement of Raman susceptibility detected from two minutesof cryogrinding b) χ”(ν)/ν2


representation in the very low-frequency range which transforms the excess of VDOS in boson peak c) in the C = O stretching region 14


European Pharmaceutical Review Volume 16 | Issue 5 | 2011


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