RAMAN SUPPLEMENT


spectrum of the stable γ-form was considered as a sensitive probe of the long-ranger order of dimer chains stabilised by strong H-bonds. Grinding is known to be a safe amorphisation method of applying both compressive and shear stresses for materials which degrade upon heating or solubilisation. By contrast to the rapid quench of the liquid state, grinding the stable γ-form gives the original opportunity to analyse the solid state amorphisation mechanism, by measuring the Raman spectra in the low-frequency and in the C = O stretching regions at different grinding times (Figure 5). The intensity decrease of the 1697 cm-1


band indicates that


grinding directly induces disordering, i.e. the disruption of low-density dimer chains leading to the loss of the long-range order at the expense of a low-density amorphous state characterised by the broad band located at 1679 cm-1


. Interestingly, pressure-induced


amorphisation of γ-IMC was observed by applying simple hydrostatic compression using a diamond-anvil cell, and interpreted as a two- step density-driven transformation19


. First, dimer chains of γ-form


transform into a denser molecular packing (similar to that of α-form) via the formation of additional H-bonding. The second step consists of a disordering process leading to a high density amorphous state suggesting a polyamorphism situation. This demonstrates that different kinds of strain induce different amorphisation mechanisms. A small amount of amorphous matter can be detected at the very


low frequencies via the enhancement of the χ”(ν) intensity leading to the observation of the boson peak in the χ”(ν)/ν2


representation


(Figure 5b, opposite), while the Raman band distinctive of the amorphous state in the C = O stretching region is quasi unobservable (Figure 5c, opposite). The analysis of the LFRS during isothermal aging at room temperature on ground amorphous IMC (Figure 6a, page 16), shows that crystallisation of γ-IMC occurs at room temperature, about 20 degrees below Tg = 43 °C. Crystallisation is first detected at low-frequencies (at t = three hours), and two hours later in the C = O stretching region (Figure 6b, page 16). Integration of the most intense Raman signature of γ-form (69 cm-1


), makes it possible


to determine the degree of crystallisation, and then the kinetics law ρ(t) plotted in Figure 7 on page 16. ρ(t) has a sigmoidal shape indicating a complete transformation which does not correspond to the overall crystallisation, since only 80 per cent of crystalline matter is determined at the end of the transformation. A fitting procedure with an Avrami-like function


Topographic Raman Imaging


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Topographic Raman Image of a Pharmaceutical Tablet


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where t0 is the time of half transformation and the exponent n


representative of the nucleation process and the dimensionality of the growth, leads to a value of nclose to 2, suggesting a crystallisation from nuclei prepared initially in the ground amorphous state5,20


. It was


also shown that addition of polyvinylpyrrolidone (PVP) inhibits crystallisation (Figure 7, page 16) without detection of additional molecular interaction21


which could explain the mechanism of stabilisation of the ground amorphous state.


Analysis of the disorder in the polymorphism of caffeine; application to the micro analyses of tablets Tabletting involves the direct compression of the API in the 40 – 400


www.europeanpharmaceuticalreview.com


European Pharmaceutical Review Volume 16 | Issue 5 | 2011


WITec GmbH, Ulm, Germany Tel. +49 (0)731 140700 info@witec.de


www.witec.de Confocal . Raman . Fluorescence . AFM . SNOM


The result is an image revealing chemical properties at the surface of the sample, even if it is rough or inclined.


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